SEARO\FHR\IVD Stephane Guichard global vaccine supply and Vaccine Research and Development in SEA

$Page 1: SEARO\FHR\IVD Stephane Guichard global vaccine supply and Vaccine Research and Development in SEA$
SEARO\FHR\IVD Stephane Guichard

global vaccine supply and Vaccine Research and Development in SEAglobal vaccine supply and Vaccine Research and Development in SEA


“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


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


Table 1:

30 vaccines available on the market

46 vaccines in the R&D pipeline


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


Investment: USD 1.9 billion to support immunization, 2006-2011

Investment: USD 1.9 billion to support immunization, 2006-2011


Examples of Vaccine Tech Transfer and Joint Venture ProgramsExamples of Vaccine Tech Transfer and Joint Venture Programs

Source IFPMA 2010


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


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


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


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%


The vaccine Market; affordability and availability



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.


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).


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.


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)


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


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


5 steps capacity building

1111 2222 3333 4444 5555

Ou

tpu

tF

ull

y fu

nct

ion

al

NR

A


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.


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


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


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


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


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.


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.


4 Providing technical inputs


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.


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.


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


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


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


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


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)


Thank you

Documents

SEARO\FHR\IVD Stephane Guichard global vaccine supply and Vaccine Research and Development in SEA