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

Outline of the presentationKey messagesContextNRA strengtheningA 10-year review of progressConstraints & challengesKey recommendations

Key messagesThe vaccine development pipeline is especially buoyant; some extremely complex products are under development; specialist regulatory oversight is neededParadigms are changing in the vaccine worldWHO 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

Context

Development of new vaccinesNorms and standardsImmunization safetyRegulatoryprocesses and qualityVaccineproduction, supplyand financing

Vaccine delivery and accelerated programmes

Monitoring and disease burden assessmentWHO vaccine portfolio:from research to disease prevention

The Vaccine Pipeline & PQ vaccines

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.

World Health Organization's Goals

Definition of Assured quality vaccines National Regulatory Authority (NRA) independent from vaccine manufacturerNRA functional (system + 6 regulatory functions)No unresolved problem with vaccines

Ensure that 100% of vaccines used in all national immunization programmes are of assured quality

NRA strengthening

Process to strengthen NRAsThe five step capacity building programme:1)Benchmarking2)NRA assessment3)Planning to address gaps (IDP)4)Implementation of plan, including technical inputs (GTN)5)Monitoring and evaluation

World Health Organization, HTP/V&B/ATT. LBelgharbi

Planning to address gaps

NRA Assessmentusing joint assessment tools(Drug & vaccine)

Follow up visits

Institutional development plan toaddress gaps

Training needs

Technicalsupport

5 days assessment

GTN placement within 1-3 months

15-24 months(6-8 months in needs muchimprovement)

NRA Network of regulatory experts

Source of vaccinesNational regulatory functions recommended for regulatory oversight of vaccines Regulatory functionsRegulatory functions CTs : Clinical trials, UN: United Nations, AEFI: Adverse Events Following ImmunizationFor countries conducting Clinical Trials

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

Country Status: country assessment of vaccine regulatory system conducted , September 1997The 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 completedNRA assessment conducted & planned Not yet conducted

Country Status: 86 country assessment of vaccine regulatory system conducted , Sept.1997 Dec 2007The 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 completedNRA assessment conducted & planned Not yet conductedNew assessment to be conducted in 2008

Global resource to raise technical skills in the field of biological regulation: the Global Training Network since 19962-BikenJapan - Producer7-Health CanadaCanada - NRA2-BioFarmaIndonesia -Producer2,5,6-NVINetherlands - Producer4-TGAAustralia - NRA2,3-NIBSCUK - NCL5-CECAL/FiocruzBrazil - Producer1-Instituto Finlay-Producer3-CECMED- NRACuba -7- AFSSAPSFrance - NRA1,9-IVPU.S.A. - Producer8-University ofCape TownSouth Africa -NRA Contract Work 9 - Licensing (for procuring countries)10. Authorisation/Monitoring of clinicalTrialsThe Global Training Network (GTN) trained 1200 staff from 100 countries since 1996 & was supported by WB, JICA, DFID,AusAid,WHO,EU,IDB,ADB,UNICEF,WHO8- MOHTunisia - MoH

Experts identified & recruited to conduct NRA assessments , 1997-2007

Number of expeerts-NRA assessment started in EMR-HQ Staff secondedTo EMRO- 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

All of the vaccine which comes through UNICEF is of Known Good Quality. Most of that directly imported is also of Known Good Quality because of the NCA functions of the producing countries which export. However, overall only 73% of DTP vaccine used in the world is of Known Good Quality, mostly due to lack of effective national control systems in some countries located in the Western Pacific and Eastern Mediterranean Regions.

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)

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

WEB site dedicated to NRA strengthening activities since 2004

Global production & NRA assessments100% of countries with high production volume/capacity assessed49 countries produce vaccines 44 countries produce consistent and important volume5 countries stopped or inconsistent/very low volume/capacitySource: WHO, NRA assessment, as of December 2007

Number of countries exercising all regulatory functions relevant to their source of vaccine, Dec.2007Number of countries65 Countries44 Countries84 Countries

All of the vaccine which comes through UNICEF is of Known Good Quality. Most of that directly imported is also of Known Good Quality because of the NCA functions of the producing countries which export. However, overall only 73% of DTP vaccine used in the world is of Known Good Quality, mostly due to lack of effective national control systems in some countries located in the Western Pacific and Eastern Mediterranean Regions.

Assured quality vaccines procured through WHO prequalification scheme , 2006used in 112 countries53% total population65 pre-qualified vaccines 24 manufacturers6 developing countries14 industrialized countries13% population

BrazilBulgariaCubaIndiaIndonesiaSenegal

AustraliaBelgiumCanadaDenmarkFranceGermanyThe NetherlandsHungaryItalyJapanRep.KoreaUSASwitzerlandSweden

Constraints & ChallengesPolitical commitment and support:Some vaccine manufacturers do not believe or wish to have independent and stronger NRA oversightPolitical 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

Constraints & ChallengesNational capacity to regulate products or contribute to WHO NRA assessments:Lack of regulatory experts with vaccines expertise in developing countriesOpportunity 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 visitsDifficulties to identify and train team leader for country assessment as it requires in depth and wide scope expertiseInstitutional Development Plan (IDP) not always followed and often re-assessment needed to update the IDP because of obsolete recommendations or changes in structure/staffNRAs staff lack of expertise/skills to assess new products

Key recommendations from 10 year review meetingNRA 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 identifiedInstitutional 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 OfficesData management & analysis: data that have been generated have not been sufficiently analyzed to learn more about systems strengthening.

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

WHO PREQUALIFICATION PROGRAMME (PQP)WHO PREQUALIFICATION PROGRAMME (PQP)The introduction of new vaccines in routine immunization is a lengthy and complex process. Historically, vaccine development has been driven by the market of industrialized countries and not by the needs of the majority of the worlds population. There are a number of initiatives under way to make expensive vaccines cheaper and adapted to developing country needs. This is best exemplified by progress being made towards developing vaccines against malaria, leishmaniasis and shistosomiasis, but also A, C and W 135 meningococcal meningitis.Norms and standards for these vaccines are set by national authorities in vaccine producing countries and, globally, by WHO Expert Committees. National regulatory authorities in both exporting and importing countries are set by national regulatory authorities and manufacturers can seek WHO pre-qualification in order to make their products available through the UNICEF or WHO global procurement schemes. The production of vaccines can then take place in industrialized countries but an expanding number of facilities in developing countries now produce high quality vaccines. Today, 60% of the measles vaccine used in developing countries originates from India. Large countries such as China, Indonesia, Brazil, but also Cuba, supply the world market..Vaccines are then introduced in routine immunization programmes with strengthened safety precautions and monitoring of covergae and impact. Ideally, vaccine development should be guided by the extent of disease burden world-wide, but market forces often go in different directions.WHO PREQUALIFICATION PROGRAMME (PQP)This slide shows the so-called vaccines pipeline. It shows on the x-axis a broad progression in time, and in the size of the bubbles the disease mortality that may be preventable through vaccination. In green, at the bottom, are the vaccines well known and used by us for the past few decades (measles, tetanus and pertussis) : this is clearly an area of disease burden that is currently preventable with the current vaccinesMostly this is addressed through the previous priority area we need to reach those children with the existing vaccines to make these mortality bubbles go away.In orange, in the middle band, are the vaccines that have recently been introduced in high and middle income countries, or which are about to become available more broadly.Through GAVI vaccines such as HepB and Hib vaccine have become much more widely available to low income countries, and have already made a major impact on disease mortality. However, especially for Hib vaccine, several countries remain hesitant to introduce EPI staff at global, regional and country levels will work with countries to examine the appropriate country data to allow the countries to make their informed decisions.For pneumococcus and rotavirus vaccines, we have been deeply involved in the preparation of the investment cases that are being submitted to GAVI for future support. Especially in the practical areas of vaccine introduction, operations and logistics and disease surveillance we believe that we have and can in future add value to the work done by the ADIPsFor the other "orange" vaccines their introduction into EPI programmes seem further off, mainly because some key data items on region specific disease burden, vaccine safety and efficacy are insufficient. As they mature, we will be able to provide similar technical support to these vaccines to the pneumococcus and rotavirus vaccinesThe vaccines outlined in red at the top of the graph will become available in the more distant future. While their development is of course of great interest, they have no direct bearing on the discussion on improving the access to vaccines

This table shows the types of vaccines that have been prequalified and the number of each type of vaccine prequalified. The vaccine types underlined indicate the production of prequalified vaccines in member states of the OIC. The OIC production of PQ vaccines are from Institute Pasteur, Dakar, Senegal - who make yellow fever vaccine & from BioFarma (who have prequalified:DT, DTP, HepB, OPV, TT and measles

WHO PREQUALIFICATION PROGRAMME (PQP)WHO has set up goals to ensure quality of vaccines that is based on the following definition: Vaccines are considered of assured quality once the national regulatory authority has an independant decision making and meet the 6 regulatory functions, however if any problem arise with a vaccine it should not remain unresolved.. This definition is based on the WHO Expert Committee on Biologicals Standardization WHO PREQUALIFICATION PROGRAMME (PQP)WHO PREQUALIFICATION PROGRAMME (PQP)WHO PREQUALIFICATION PROGRAMME (PQP)WHO PREQUALIFICATION PROGRAMME (PQP)WHO PREQUALIFICATION PROGRAMME (PQP)WHO PREQUALIFICATION PROGRAMME (PQP)WHO PREQUALIFICATION PROGRAMME (PQP)WHO PREQUALIFICATION PROGRAMME (PQP)WHO PREQUALIFICATION PROGRAMME (PQP)WHO PREQUALIFICATION PROGRAMME (PQP)