searo\fhr\ivd stephane guichard global vaccine supply and vaccine research and development in sea
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SEARO\FHR\IVD Stephane Guichard
global vaccine supply and Vaccine Research and Development in SEAglobal vaccine supply and Vaccine Research and Development in SEA
SEARO\FHR\IVD Stephane Guichard
“More vaccines have been developed and others are already in the late stages of clinical trials, making this decade the most productive in the history of vaccine development”.
WHO, State of the world’s vaccines and immunization, Third edition, 2009, Executive summary
UNICEF Procurement value of vaccines increased 5 folds from $220 millions in 2002 to $1,03 billions in 2011 with 2.5 billions vaccines doses supplied to 103 countries
UNICEF Supply Division Annual Report 2011
SEARO\FHR\IVD Stephane Guichard
Source:This analysis represents a synthesis of various sources including: Frost & Sullivan, Datamonitor, Theta Reports, Genesis
Rapid growthRapid growth
Traditional + Combos
New Vaccines
Therapeutic Vaccines
1990 2001 2003 2005 2007 2009
5.000
30.000
10.000
15.000
20.000
25.000
6,8
8,8
11,5
15,1
18,4
1,5
3,5
Billion of US$
2,0
0,2
SEARO\FHR\IVD Stephane Guichard
Table 1:
30 vaccines available on the market
46 vaccines in the R&D pipeline
SEARO\FHR\IVD Stephane Guichard
Vaccine R&D in SEAVaccine R&D in SEA
Compare to the quantity of vaccine produced in the region R&D activities are limited
To foster greater contribution of DC countries in vaccine R&D efforts requires a good understanding of IPR, greater Government support and Incentives, better synergy with University and research institutes and a strong regulatory framework
New policy innovation including IFFIm and AMC stimulated transfer of technology and production of Hib and pantavallent vaccines
SEARO\FHR\IVD Stephane Guichard
Investment: USD 1.9 billion to support immunization, 2006-2011
Investment: USD 1.9 billion to support immunization, 2006-2011
SEARO\FHR\IVD Stephane Guichard
Examples of Vaccine Tech Transfer and Joint Venture ProgramsExamples of Vaccine Tech Transfer and Joint Venture Programs
Source IFPMA 2010
SEARO\FHR\IVD Stephane Guichard
Best Selling Vaccines 2007- 2009Best Selling Vaccines 2007- 2009
Brand Name
®
Generic Name Company Indication Sales $ billions
2007 2008 2009
Prevnar Pneumococcal
ConjugateVaccine
Pfizer Pneumococcal
Dis
2.44 2.7 3.0
Gardasil Human Papillomavirus Quadrivalent Vaccine
Merck Cervical Cancer 1.44 2.3 1.66
Fluarix, FluLaval H1N1 Pandemrix
Influenza Vaccines GSK 1.71
Fluzone
Pandemic
Influenza Vaccines Sanofi Aventis Pasteur
Influenza 1.1 1.2 1.45
Cultura Influenza Vaccines Novartis 1.12
Engerix-B, Havrix, Twinrix
Hepatitis A & B
Vaccines
GSK Hepatitis 1.1 1.2 1.04
Infanrix, Pediarix
Children Vaccine GSK Diphtheria,
tetanus, and pertussis
1.1 1.2 1.01
SEARO\FHR\IVD Stephane Guichard
Vaccine producers in the market (source: Mercer study to GAVI, 2002)
Vaccine producers in the market (source: Mercer study to GAVI, 2002)
US multinationals Europeanmultinationals
OECDlocals
Emerging suppliers Developing countrylocal
Product range
Narrow Broad Narrow Narrow-Moderate
Narrow
Scale Low High Low Moderate-High Low-High
Customer focus
Mostly high income All buyer segments
Mostly in country In country and other low moderate
income buyers
All in country
R&D activity High High Low Low-Moderate Low
Producers Merck, Wyeth Sanofi-Pasteur (France), GSK
(Belgium), Chiron (Italy)
SSI (Denmark), CSL (Australia), Powderject
SII (India) ,Biofarma
(Indonesia), Green Cross (Rep.Korea)
State owned producers: China,
Egypt, Mexico,Viet Nam,Thailand
SEARO\FHR\IVD Stephane Guichard
The UNICEF : buying 40% of the global volume of vaccine doses, mainly EPI vaccines, but representing only 5% of market value
The UNICEF : buying 40% of the global volume of vaccine doses, mainly EPI vaccines, but representing only 5% of market value
40%5%
Global Volume of Doses Global Value of Doses
SEARO\FHR\IVD Stephane Guichard
Vaccine producing1990 :63 countries2010 :44 countries
Majors vaccines producing countriesChina……………..23%India......………….30%Indonesia………..10%S.Korea……..…....5%Brazil……………....3%Bulgaria……………5%France……………..8%Russia……………..2%Italy………………..3%Belgium…………...5%Other countries….5%
8%
23%
30%
10%
5%
SEARO\FHR\IVD Stephane Guichard
The vaccine Market; affordability and availability
SEARO\FHR\IVD Stephane Guichard
SEARO\FHR\IVD Stephane Guichard
Vaccine clinical Trials in SEA
India Influenza Vaccine
• Phase IV: Direct and Indirect Protection by Influenza Vaccine Given to Children in India
Rotavirus vaccine
• Phase I: Exploration of the Biologic Basis for Underperformance of Oral Polio and Rotavirus Vaccines in INDIA
• Phase II: A Randomized, Double-Blind, Placebo Controlled Study to Assess Safety and Tolerability of
LAV Pentavalent Rotavirus Vaccine
• Phase I&II: Randomized, Double-blind, Placebo-controlled, Dosage Selection Study to Evaluate the Safety, Tolerability, and Immunogenicity of a 3-dose
Series of LAV Tetravalent Rotavirus Vaccine.
• Phase I&II: Randomized, Double-Blind, Placebo Controlled Study To Assess the Safety And Tolerability
Of LAV Pentavalent Rotavirus.
Cholera vaccine
• Phase IV: A Open Labeled Controlled Trial to Evaluate the Immune Response of a Boosting Regimen With a Killed Whole Cell Oral Cholera Vaccine, in
Previously Immunized Adults and Children.
• Phase II: Randomized controlled trial to evaluate the Immunogenicity of 2 Doses of whole-cell oral cholera vaccine with 2 vaccination schedules.
• Phase IV: An open label trial to evaluate the safety and immunogenicity of indigenously manufactured killed
(O1 and O139) whole cell oral cholera vaccine.
Bangladesh
Influenza Vaccine
• Phase II: Assessment of the Safety and Immunogenicity of a Single Dose of Intranasal Seasonal Trivalent LAV influenza vaccine among children 24- 59 months.
• Phase III: Influenza Vaccine Efficacy Against Childhood Pneumonia in an Urban Tropical Setting in Bangladesh
Rotavirus
• Phase I: Exploration of the Biologic Basis for Underperformance of Oral Polio and Rotavirus Vaccines in Bangladesh
Cholera Vaccine
• Phase IV: Introduction of Cholera vaccine in Bangladesh: “Impact Evaluation of Cholera vaccine and behavior change interventions in Urban Dhaka.
SEARO\FHR\IVD Stephane Guichard
Current influenza vaccine clinical trials in SEACurrent influenza vaccine clinical trials in SEAVaccine clinical Trials in SEA
Thailand
Dengue Vaccine
• Phase II: A double-blind, randomized, placebo-controlled, age descending and expansion study to investigate safety, Immunogenicity of a Tetravalent Chimeric Dengue Vaccine in Healthy Volunteers of age 1.5 - 45 Years.
• Phase III: Efficacy and safety of a novel tetravalent dengue vaccine in healthy children aged 2 to 14 Years in Asia(Indonesia, Malaysia, Philippines, Thailand and Vietnam)
Indonesia
Dengue
• Phase III: Efficacy and safety of a novel tetravalent dengue vaccine in healthy children aged 2 to 14 Years in Asia(Indonesia, Malaysia, Philippines, Thailand and Vietnam).
SEARO\FHR\IVD Stephane Guichard
Vaccine of assured quality issuesVaccine of assured quality issues
Vaccine manufacturers were able to benefit from global financing opportunities to invest in production of new products
NRA are challenged with more sophisticated products and regulatory procedures (e.g: vaccine testing, use of placebo in clinical trials,..), limited funding from Governments and capacity to keep up with expertise requirements
In 2012 there are risks of shortages with some vaccines including OPV (due to delisting of 2 manufacturers from WHO list of PQ vaccines) and DTP (due to underestimate of needs with introduction of pantavallent vaccine.
SEARO\FHR\IVD Stephane Guichard
Vaccine of assured quality and WHO support to NRA capacity buildingVaccine of assured quality and WHO support to NRA capacity building
World Health Organization ‘s GoalsWorld Health Organization ‘s Goals
Ensure that “100%”“100%” of vaccines used in all national immunization programmes are of assured quality
Definition of “Assured quality Assured quality vaccinesvaccines”
– National Regulatory Authority (NRA) independent from vaccine manufacturer
– NRA fully functional (system + 6 regulatory functions)
– No unresolved reported problem with vaccine
Guided by Experts Guided by Experts Committee on Committee on Standardization of Standardization of Biologicals (ECBS) Biologicals (ECBS) recommendationsrecommendationson safety, efficacy and on safety, efficacy and quality issued in WHO quality issued in WHO Technical Report Series Technical Report Series (TSR)(TSR)
SEARO\FHR\IVD Stephane Guichard
Aventis Pasteur, Canada DTP, measles
Aventis Pasteur, France DT, dT, DTP, DTP-Hib, OPV, TT, measles, MMR, Hib, yellow fever, meningococcal A + C
Biken, Japan measles
Bio Farma, Indonesia DT, DTP, OPV, TT, TT filled in Uniject, measles
Biomanguinhos, Brazil yellow fever
Center for Genetic Engineering and Biotechnology, Cuba Hepatitis B (recombinant)
Cheil Jedang, Korea Hepatitis B (plasma derived)
Chiron Behring, Germany DTP, Rabies
Chiron Behring, India Rabies
Chiron Vaccines, Italy DTP, MMR (measles, mumps,
rubella combination), MR (measles, rubella combination), OPV, measles, Hib, DTP-Hib
CSL, Australia DT, DTP, TT
Evans Vaccines (formerly Medeva, U.K.) yellow fever
GlaxoSmithKline, Belgium Hepatitis B, Hib, OPV, meningococcal A + C, DTP-Hep B, DTP-Hep B to be combined with Hib (pentavalent), measles, MMR
GreenCross Vaccine Corporation, Korea Hepatitis B (recombinant)
Institut Pasteur Dakar, Senegal yellow fever
Japan BCG BCG
Lucky Goldstar, Korea Hepatitis B (recombinant)
Merck and Co. Inc, USA Hepatitis B, Liquid Pedvax HIB
National Center for Infectious and Parasitic Diseases, Intervax, Bulgaria
BCG
SBL Vaccin AB, Sweden Inactivated oral cholera
Serum Institute of India BCG, DT, dT, DTP, TT, MR, measles
Shantha Biotechnics Private Ltd., India Hepatitis B (recombinant)
Statens Seruminstitut, Denmark BCG
Wyeth Lederle Vaccines and Pediatrics, USA
Hib
WHO list of Pre-Qualified vaccines for procurement through UN agencies
SEARO\FHR\IVD Stephane Guichard19
The National Regulatory Authority (NRA) is responsible for the quality, safety and efficacy of vaccines.
NRA is the corner stone of a national policy to develop production of vaccine of assured quality
SEARO\FHR\IVD Stephane Guichard
20
Supervision of clinical trialsSupervision of clinical trials
Vaccine regulatory processVaccine regulatory process
Pre-marketing phasePre-marketing phase Post Marketing phasePost Marketing phase
AEFIsAEFIsLot releaseLot release
GMP inspections
GMP inspections
GMP assessment
GMP assessment
Applicants dossier
Applicants dossier
Clinical EvaluationClinical Evaluation
Product evaluation
Product evaluation Quality Control Quality Control
Marketing Authorization (M.A.)Marketing Authorization (M.A.)
Function 1Marketing Autorization &
Activities licensing
Function 3Lot release
Function 4Laboratory
access
Function 2Postmarketing
AEFI
Function 5Regulatoryinspections
Function 6: Supervision of clinical trials
SEARO\FHR\IVD Stephane Guichard
5 steps capacity building
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SEARO\FHR\IVD Stephane Guichard
1 Development of NRA assessment tools
Engage stakeholders on Engage stakeholders on capacity developmentcapacity development
NRA Assessment tool NRA Assessment tool development processdevelopment process
All stakeholders share ownership in the process of development
Regulatory experts from NRA in high, middle and low incomes countries to benchmark vaccine regulatory system
Engaging all stakeholders for more effective decision making and transparent work process.
Tools tested in several countries by vaccine regulatory experts and endorsed by international vaccine safety peer group committees.
Engage stakeholders on Engage stakeholders on capacity developmentcapacity development
NRA Assessment tool NRA Assessment tool development processdevelopment process
All stakeholders share ownership in the process of development
Regulatory experts from NRA in high, middle and low incomes countries to benchmark vaccine regulatory system
Engaging all stakeholders for more effective decision making and transparent work process.
Tools tested in several countries by vaccine regulatory experts and endorsed by international vaccine safety peer group committees.
SEARO\FHR\IVD Stephane Guichard
1997 1998
1999
2002 20042001 2007 2009 2011
First draft discussed in an inter-country workshop organized in WHO’s Western Pacific Region, in Manila.
First field testing of the vaccines NRA assessment tools in Iran, Egypt, Pakistan then in all EMRO countries . Assessment tool first published
Combined set of indicators developed by experts from vaccines and drugs departments, to assess the functions of the NRA for vaccines and medicines
Joint revision including medicines and vaccines experts.
Revised in consultation with PQ to align NRA function with PQ requirements
Concept of critical indicators established with NRA experts.
Revised in a consultation meeting to improve clarity in the text of indicators.
Include QMS requirement for all functions and to expand content of function 6 as regulatory oversight of clinical trials
Updated after field test in several countries, amendment re 3 sub-indicators under indicator 2 in PMS/AEFI function
Revision of NRA indicators and commitment of medicines to work in close collaboration for NRA capacity building.
NRA assessment tool is developed with active participation
and consensus of NRA experts from high, middle and low
incomes countries
Development of methodology and assessment tools 1997 - 2011
SEARO\FHR\IVD Stephane Guichard
2 Conducting assessments against NRA indicators
Assess Capacity needs and Assess Capacity needs and assetsassets
Field Assessment of NRA Field Assessment of NRA capacitycapacity
Assessing existing capacity through engagement with stakeholders to identify areas with training needs, define the priorities and estimate capacity to be incorporated into local and institutional development strategies
Mixed of regional and international assessors engage in discussions during field assessments turned into large networks of vaccine regulatory experts from high middle and low incomes countries interacting to solve regulatory issues.
UNDP argues that capacity building that is not rooted in a comprehensive study will be restricted to training alone which may not lead to sustained results.
Used of standards indicators results in very specific interventions categorized into training support and technical support
Assess Capacity needs and Assess Capacity needs and assetsassets
Field Assessment of NRA Field Assessment of NRA capacitycapacity
Assessing existing capacity through engagement with stakeholders to identify areas with training needs, define the priorities and estimate capacity to be incorporated into local and institutional development strategies
Mixed of regional and international assessors engage in discussions during field assessments turned into large networks of vaccine regulatory experts from high middle and low incomes countries interacting to solve regulatory issues.
UNDP argues that capacity building that is not rooted in a comprehensive study will be restricted to training alone which may not lead to sustained results.
Used of standards indicators results in very specific interventions categorized into training support and technical support
SEARO\FHR\IVD Stephane Guichard
Country Status: 176 country assessment of vaccine regulatory system conducted for 97 countries, as of 2011
Country Status: 176 country assessment of vaccine regulatory system conducted for 97 countries, as of 2011
SEARO\FHR\IVD Stephane Guichard
3 Formulate Institutional Development Plan
development responsedevelopment responseElaborate NRA Institutional Elaborate NRA Institutional development plandevelopment plan
Institutional arrangements Policies, procedures, resources management
Identify problems of system, process, performance outcomes.
Leadership Identify leading institutions, program, initiatives that support the development plan
Knowledge is the foundation of capacity
Performance need assessments and training and technical supports
Accountability to monitor and evaluate institutions
Accountability through measurable indicators of functionality for each of the 6 vaccine regulatory functions required.
Formulate a capacity Elaborate NRA Institutional development plan
Institutional arrangements Policies, procedures, resources management
Identify problems of system, process, performance outcomes.
Leadership Identify leading institutions, program, initiatives that support the development plan
Knowledge is the foundation of capacity
Performance need assessments and training and technical supports
Accountability to monitor and evaluate institutions
Accountability through measurable indicators of functionality for each of the 6 vaccine regulatory functions required.
SEARO\FHR\IVD Stephane Guichard
Institutional Development Plan processInstitutional Development Plan process
•NRA assessment findings discussed with Government counterparts
•Formulation of recommendations and consensus on priorities
•Technical support and training support components identified
•Budget requirements estimated and Proposals for funds raising elaborated
•Activities for NRA capacity building included in regional and country workplan
•Implementation of activities in cooperation with WHO HQ and regional offices
•Monitor changes and make adjustments if required and IDP updated
•Reassessment conducted every 2 years.
SEARO\FHR\IVD Stephane Guichard
4 Providing technical inputs
Assess Capacity needs and Assess Capacity needs and assetsassets
Providing technical inputs Providing technical inputs
Inclusion of multiple system national, institutional.
In-country training and training through GLO, placement fellowship placement, study tours, etc ….
continuous monitoring to measures changes and make adjustment, to measures outputs and outcomes.
Technical support for “hand-on”practices including GMP joint audits, parallel review for MA, experts committee groups to conduct AEFI investigation and causality assessments.
Assess Capacity needs and Assess Capacity needs and assetsassets
Providing technical inputs Providing technical inputs
Inclusion of multiple system national, institutional.
In-country training and training through GLO, placement fellowship placement, study tours, etc ….
continuous monitoring to measures changes and make adjustment, to measures outputs and outcomes.
Technical support for “hand-on”practices including GMP joint audits, parallel review for MA, experts committee groups to conduct AEFI investigation and causality assessments.
SEARO\FHR\IVD Stephane Guichard
BikenJapan - Producer
Health CanadaCanada - NRA
BioFarmaIndonesia -Producer
NVINetherlands - Producer
TGAAustralia - NRA
NIBSCUK - NCL
CECAL/FiocruzBrazil - Producer
Instituto Finlay
CECMED - NRA Cuba
-AFSSAPS
France - NRA
IVPU.S.A. - Producer
University ofCape TownSouth Africa -NRA Contract Work
MOHTunisia - MoH
Moscow - NRA
Tarassevitch
SEARO\FHR\IVD Stephane Guichard
Training strategy and methodology for NRA capacity BuildingTraining strategy and methodology for NRA capacity Building
Training needs identified
Training conducted through WHO Global Learning Opportunity scheme involving several countries
In-country training programme usually involving one or 2 countries NRA specialists
Placement through WHO fellowship involving 2 or 3 NRA technicians and study tours in partnership with NRA/NCL
In-country “hand on” practices as follow-up to formal training workshop including parallel review for MA; joined regulatory inspection, formal expert review committee to conduct AEFI causlaity assessment
SEARO\FHR\IVD Stephane Guichard
5 Monitoring and evaluations
Evaluate capacity Evaluate capacity developmentdevelopment
Continues monitoringContinues monitoring
Monitoring changes in the institution performances
Follow-up assessments conducted very 2 years
Evaluation should be based on changes in performance in the four main issues; institutional arrangements, leadership, knowledge and accountability.
Periodic reviews and updates of assessments tools and training materials to meet new regulatory requirements with introduction of new and under-utilized vaccines.Development of road map for mid and long term capacity bldg
Evaluate capacity Evaluate capacity developmentdevelopment
Continues monitoringContinues monitoring
Monitoring changes in the institution performances
Follow-up assessments conducted very 2 years
Evaluation should be based on changes in performance in the four main issues; institutional arrangements, leadership, knowledge and accountability.
Periodic reviews and updates of assessments tools and training materials to meet new regulatory requirements with introduction of new and under-utilized vaccines.Development of road map for mid and long term capacity bldg
SEARO\FHR\IVD Stephane Guichard
Networking of NRA expertsNetworking of NRA experts
• NRA assessments conducted by regulatory experts from high, medium and low income countries
• NRA assessment tool has brought some standardizations of procedures at regional and global level
• Data base of approximately 350 regulatory experts including contact details and CV managed by WHO HQ
• High level of cooperation among NRA experts from high, middle and low income countries was achieved through the process of conducting assessment, implementing training activities and providing technical supports
SEARO\FHR\IVD Stephane Guichard
RecommendationsRecommendations
Legal Basis
Harmonization of regulatory framework
Capacity building
Guidelines and expertise development are priorities. Legal framework should not be a barrier for regulatory activities
Need to distinguish between technical and political levels of harmonization. WHO does not interferes with political decisions on harmonization
Need to develop NRA capacity for new vaccines (e.g.: polysaccharide vaccines)
SEARO\FHR\IVD Stephane Guichard
Thank you
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