1. WHO Prequalification of Diagnostics, Medicines and Vaccines - 3rd Consultative Stakeholders Meeting Review - 10 years of strengthening vaccines regulatory capacity David Wood and Lahouari Belgharbi, Quality Safety and Standards (QSS); Immunization, Vaccines and Biologicals (IVB); Family and Community Health (FCH); WHO HQ, Geneva

2. Outline of the presentation  Key messages  Context  NRA strengthening  A 10-year review of progress Constraints & challenges Key recommendations

3. Key messages  The vaccine development pipeline is especially buoyant; some extremely complex products are under development; specialist regulatory oversight is needed  Paradigms are changing in the vaccine world 100%  WHO is committed to support countries to ensure and sustain that 100% of vaccines used in all national immunization programmes are of assured quality – NRA strengthening is one strategy to attain this goal

4. Context

5. Development of new vaccines Norms and standards Immunization safety Regulatory processes and quality Vaccine production, supply and financing Vaccine delivery and accelerated programmes Monitoring and disease burden assessment WHO vaccine portfolio: from research to disease prevention

6. The Vaccine Pipeline & PQ vaccines

7. Vaccine Manufacture shift from Industrial to Developing Countries  1992, 100% of vaccine purchased by UNICEF from Industrial Nations  2000, 53% of vaccines purchased are from Developing Nations, which include: 25% of Polio, 90% of Measles, 85% of Yellow Fever, 79% of Hep. B.  1997-2000, 50% of Industrial Nations left BCG, DTP and TT manufacture  7-10 manufacturer left measles production, leaving one country supplying >90% of the UNICEF needs – risk to vaccine security.

8. World Health Organization's Goals Assured quality vaccines Definition of “Assured quality vaccines” National Regulatory Authority (NRA) independent from vaccine manufacturer NRA functional (system + 6 regulatory functions) No unresolved problem with vaccines Guided by Expert Committee on Standardization of Biologicals (ECBS) recommendations on safety, efficacy and quality issued in WHO Technical Report Series (TRS) “100%” Ensure that “100%” of vaccines used in all national immunization programmes are of assured quality

9. NRA strengthening

10. Process to strengthen NRAs The five step capacity building programme: 1)Benchmarking 2)NRA assessment 3)Planning to address gaps (IDP) 4)Implementation of plan, including technical inputs (GTN) 5)Monitoring and evaluation

11. Source of vaccines UN agency Procure Produce National regulatory functions recommended for regulatory oversight of vaccines Regulatory functions Regulatory functions CTs : Clinical trials, UN: United Nations, AEFI: Adverse Events Following Immunization Marketing Autorization & Licensing activities Laboratory access Regulatory inspections Lot release Authorization & monitoring of CTs Postmarketing: AEFI Regulatory system For countries conducting Clinical Trials

12. A 10-year review of progress, revision of NRA benchmarking system and a look to the future. Geneva 17-19 Dec 2008 Strengthening vaccine regulatory capacity Quality, Safety & Standards (QSS) Immunization, Vaccines & Biologicals (IVB)

13. Country Status: country assessment of vaccine regulatory system conducted, September 1997 The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. NRA assessment completed NRA assessment conducted & planned Not yet conducted

14. Country Status: 86 country assessment of vaccine regulatory system conducted, Sept.1997 – Dec 2007 The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. NRA assessment completed NRA assessment conducted & planned Not yet conducted New assessment to be conducted in 2008

15. 2-Biken Japan - Producer 7-Health Canada Canada - NRA 2-BioFarma Indonesia -Producer 2,5,6-NVI Netherlands - Producer 4-TGA Australia - NRA 2,3-NIBSC UK - NCL 5-CECAL/Fiocruz Brazil - Producer 1-Instituto Finlay -Producer 3-CECMED - NRA Cuba Participants 1. NRA Staff with Government Plan 2. Staff of Manufacturer with NRA & Strategic Plan 3. NRA Staff and EPI Staff from vaccine procuring countries (for AEFI course only) Courses 1 –Regulatory inspections 2 - Quality Control Methods 3 - Laboratory Quality Systems 4 - Licensing (for producing countries) 5 - Animal Husbandry 6 - Short Course in DTP 7 - Lot Release and Lab Access 8 -PostmarketingSurveillance/AEFI - 7- AFSSAPS France - NRA 1,9-IVP U.S.A. - Producer 8-University of Cape Town South Africa -NRA Contract Work Global resource to raise technical skills in the field of biological regulation: the Global Training Network since 1996 9 - Licensing (for procuring countries) 10. Authorisation/Monitoring of clinical Trials 1200 1996 & was supported by WB, JICA, DFID,AusAid,WHO,EU,IDB,ADB,UNICEF,WHO The Global Training Network (GTN) trained 1200 staff from 100 countries since 1996 & was supported by WB, JICA, DFID,AusAid,WHO,EU,IDB,ADB,UNICEF,WHO 8- MOH Tunisia - MoH

16. Experts identified & recruited to conduct NRA assessments, 1997-2007 Number of expeerts -NRA assessment started in EMR -HQ Staff seconded To EMRO -NRA assessment started in EMR -HQ Staff seconded To EMRO - 86 NRA assessments - 76 follow up visits conducted - Fundraising increased: WHO, Australia, Japan, WB, DFID, USAID,EDCTP - 86 NRA assessments - 76 follow up visits conducted - Fundraising increased: WHO, Australia, Japan, WB, DFID, USAID,EDCTP -HQ staff reassigned to HQ to coordinate NRA activities : -initial budget $44.000 -HQ staff reassigned to HQ to coordinate NRA activities : -initial budget $44.000

17. The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. NRA regulatory experts 350 Regulatory experts recruited from national regulatory authorities (Sept 1997- Dec.2007)

18. Databases : 8 modules developed for planning, assessment, experts & monitoring

19. WEB site dedicated to NRA strengthening activities since 2004

20. Global production & NRA assessments 100% of countries with high production volume/capacity assessed 49 countries produce vaccines 44 countries produce consistent and important volume 5 countries stopped or inconsistent/very low volume/capacity Source: WHO, NRA assessment, as of December 2007

21. Number of countries exercising all regulatory functions relevant to their source of vaccine, Dec.2007 Number of countries 65 Countries 44 Countries 84 Countries

22. Assured quality vaccines procured through WHO prequalification scheme, 2006 used in 112 countries 53% total population 65 pre-qualified vaccines 65 pre-qualified vaccines 24 manufacturers 24 manufacturers 6 developing countries 14 industrialized countries Brazil Bulgaria Cuba India Indonesia Senegal 13% population Australia Belgium Canada Denmark France Germany The Netherlands Hungary Italy Japan Rep.Korea USA Switzerland Sweden

23. Constraints & Challenges Political commitment and support:  Some vaccine manufacturers do not believe or wish to have independent and stronger NRA oversight  Political commitment to support in country NRA activities is lacking in several countries Global supply of vaccine:  Risk of global shortage of critical vaccines in case of failure of NRA in producing countries to exercise all six functions

24. Constraints & Challenges National capacity to regulate products or contribute to WHO NRA assessments:  Lack of regulatory experts with vaccines expertise in developing countries  Opportunity costs of mentoring and training of experts for assessments because of the limited number of assessments each expert performs  Government not always keen to release national experts for WHO assessments, training and follow up visits  Difficulties to identify and train team leader for country assessment as it requires in depth and wide scope expertise  Institutional Development Plan (IDP) not always followed and often re-assessment needed to update the IDP because of obsolete recommendations or changes in structure/staff  NRAs staff lack of expertise/skills to assess new products

25. Key recommendations from 10 year review meeting NRA assessments have been key to assist countries to strengthen their regulatory system and develop plan (IDP) to meet prequalification requirements, the activities should continue by improving the following areas:  Experts: The standards of the experts, and their experience and understanding of the regulatory process, vary. Further consideration should be given to recruitment and training of experts for this work.  Improved synergies : between the WHO vaccines and medicines NRA assessment processes should be identified  Institutional Development Plan (IDP): needs to be ongoing, subject to regular (but not too frequent) review, and it needs to have built in to it sustained financial support and political will.  Decentralization: There needs to be increasing involvement of the WHO Regional Offices  Data management & analysis: data that have been generated have not been sufficiently analyzed to learn more about systems strengthening.

26. WHO Prequalification of Diagnostics, Medicines and Vaccines - 3rd Consultative Stakeholders Meeting Review - 10 years of strengthening vaccines regulatory capacity David Wood and Lahouari Belgharbi, Quality Safety and Standards (QSS); Immunization, Vaccines and Biologicals (IVB); Family and Community Health (FCH); WHO HQ, Geneva