Evaluating the acceptability of vaccine and vaccination ... · Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008. Process to strengthen NRAs The five step capacity building programme

The regulatory processThe regulatory process

Evaluating the acceptability of vaccine and vaccination programmes: an individual and p g

public health perspective

Annecy, Les Pensières July 7-9, 2008Annecy, Les Pensières July 7 9, 2008

Dr. Nora Dellepiane, Scientist WHO/IVB/QSS July 2008

OutlineOutline

Vaccines of assured quality

Recommended regulatory functions and source of vaccines. WHO support to strengthen regulatory f tifunctions

New vaccines: New challengesNew vaccines: New challenges

WHO innovative approaches to support strengthening f l t itof regulatory capacity

Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008

Vaccines of assured qualityq y


Contribution toWorld Health Organization Goal

Contribution toWorld Health Organization Goalgg

Ensure that “100%”“100%” of vaccines Ensure that 100%100% of vaccines used in all national immunization

programmes are of assured quality

D fi iti f “A d litA d lit Definition of “Assured quality Assured quality vaccinesvaccines” National Regulatory Authority (NRA)

Guided by Expert Guided by Expert Committee on Committee on Standardization of Standardization of Bi l i l (ECBS)Bi l i l (ECBS) National Regulatory Authority (NRA)

independently controls the quality of vaccines in accordance with the six specified functions defined by WHO

Biologicals (ECBS) Biologicals (ECBS) recommendationsrecommendationson on safetysafety, , efficacy efficacy

dd litlit i di dspecified functions defined by WHO No unresolved confirmed reports of quality

related problems

and and qualityquality issued issued in WHO Technical in WHO Technical Report Series (TRS)Report Series (TRS)


Recommended regulatory functions d f i WHOand source of vaccines. WHO

support to strengthen regulatory pp g g yfunctions


Regulatory functions depending i

Vaccine source

on vaccine source

Vaccine sourceUN agency Direct

ProcurementProduction

Regulatory functions

Licensing

Regulation System

Lot release

AEFI monitoring

Functionsassuredby NRA of

Functionsassuredby NRA of

Access to laboratory

L t r a

y

producingcountry and WHO PQ system

yproducingcountry and WHO PQ system

Fuctions assuredby NRA ofproducing

Fuctions assuredby NRA ofproducing

Regulatory inspections Authorization of


WHO PQ systemWHO PQ system countrycountryclinical trials

Regulatory guidance – WHO norms and standards

Regulatory guidance – WHO norms and standardsstandardsstandards

Global written standardsGlobal written standards Global measurement Global measurement

Support for the evidence base for standards

standardsstandards


WHO Global written standardsWHO Global written standards

Technical specifications that help define safe and efficacious vaccines. These are intended to be scientific and advisory in nature

Guidance for national regulatory authorities and manufacturers on international regulatory expectations for the production andinternational regulatory expectations for the production and quality control of vaccines, non-clinical and clinical evaluation of vaccines

Facilitate international harmonisation of vaccine licensure

Living documents revised in response to scientific advances


Use of WHO guidance and standardsUse of WHO guidance and standards

The WHO Recommendations on production and quality The WHO Recommendations on production and quality control of vaccines are used as:

- the basis of national regulations in many countries

the technical specifications against which compliance- the technical specifications against which compliance is assessed for the purposes of pre-qualification of vaccine supply by UN agenciesvaccine supply by UN agencies


Process to strengthen NRAsProcess to strengthen NRAsThe five step capacity building programmeThe five step capacity building programme

1)B h ki1)Benchmarking

2)NRA assessmentPlanning to address gaps

NRA Network of regulatory experts3)Planning to address gaps (IDP)

4)Implementation of plan, NRA NRA T i i Training

g y p

) p e e tat o o p a ,including training courses (GTN), technical inputs, in country workshops

NRA Assessmentusing joint

assessment

NRA Assessmentusing joint

assessmentFollow up

visitsFollow up

visits

Institutional development

plan to

Institutional development

plan to

Training needs

Training needs

country workshops

5)Monitoring and evaluation

assessment tools

(Drug & vaccine) tools

(Drug & vaccine)

visitspaddress gapsaddress gaps Technical

supportTechnicalsupport

15-24 months(6-8 months

5 days assessment GTN placementwithin 1-3 months

(6 8 monthsin needs muchimprovement)


Country Status: country assessment of vaccine regulatory system conducted , September 1997

NRA assessments conducted

NRA assessments completed

& planned

Not yet conducted


T

y

Country Status: 86 country assessment of vaccine regulatory system conducted , Sept.1997 – Dec 2007

NRA assessments conducted & planned

NRA assessments completedNot yet conductedNew assessments to be conducted in 2008


New vaccines: New challenges


The Vaccine Pipeline & PQ vaccinesThe Vaccine Pipeline & PQ vaccines

MalariaTB

HIV/AIDS

Future

CholeraPneumo (conj)

RotavirusHPVMening (conj)

Dengue

YF Influenza RubellaHepB

Hib (conj)

Typhoid

CholeraUnderutilized

Vaccines

Tetanus

YF Influenza

Polio

Measles

JE Rubella

Traditional EPI

1960 1980 2000// //Diphtheria

Pertussis

Polio

Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008Vaccine Development Pipeline

1960 1980 2000

Key messagesKey messagesy gy g

The vaccine development pipeline is especially buoyant; some complex products are under development; specialist regulatory oversight is needed

WHO is committed to support countries to ensure and WHO is committed to support countries to ensure and sustain that 100%100% of vaccines used in all national immunization programmes are of assured quality – NRA p g q ystrengthening activities and other innovative approaches are being applied to attain this goal


New challengesNew challengesNew challengesNew challenges

R l ti f i Regulation of new vaccines :– Responsibility now falls more on Developing Countries using these

vaccines and less on Industrialized Countries where they are producedC t i h i ffi i t ti d i t d t d– Countries have insufficient expertise and experience to assess data and dossiers (Manufacturing, preclinical and clinical data, etc.)

NRAs must acquire new skills

Clinical trials for new vaccinesA b i i ANY t tt th ti / t th f th i– Are being run in ANY country, no matter the expertise/strength of their National Regulatory Authority

Quality of the trials must be guaranteed


Responding to challengesResponding to challengesResponding to challengesResponding to challenges

1 Development of new support mechanisms for1. Development of new support mechanisms for regulatory authorities

2 D l t f l t th2. Development of new regulatory pathways


New Support Mechanisms for National Regulatory AuthoritiesNew Support Mechanisms for

National Regulatory AuthoritiesNational Regulatory AuthoritiesNational Regulatory Authorities Establishment of Developing Countries Vaccines Establishment of Developing Countries Vaccines

Regulators Network (DCVRN) in 2004

Establishment of African Vaccine Regulatory Forum (AVAREF) in 2006

Development of new Global Training Network Courses and country workshops on a needs basisCourses and country workshops on a needs basis

Sentinel Network to monitor safety during introduction of novel vaccines and DTP based combinations


New Regulatory Support Mechanisms1. Establishment of the Developing Countries

New Regulatory Support Mechanisms1. Establishment of the Developing Countries

Brazil, Cuba, China, India, Indonesia

1. Establishment of the Developing CountriesVaccine Regulators Network (Global)

1. Establishment of the Developing CountriesVaccine Regulators Network (Global)

Korea, Russia, South Africa andThailand


1. Developing Countries Vaccine Regulators Network

1. Developing Countries Vaccine Regulators NetworkVaccine Regulators NetworkVaccine Regulators Network

ObjectivesPromote and support the strengthening of the regulatory capacity of

NRAs f th l ti f li i l t i l l d li i l t i l d tfor the evaluation of clinical trial proposals and clinical trial data through expertise and exchange of relevant information.

Modus OperandiMeetings twice a year Discuss critical aspects to be considered for the review of clinical data

for registration of novel vaccinesDevelop procedures, forms and other relevant documents to harmonize

regulation of clinical trials and evaluation of clinical trial dataExchange of information and mutual supportProvide support to other countries in their region of influence (i.e. SA


and Indonesia

1. African Vaccine Regulators Forum (AVAREF) established in 2006

1. African Vaccine Regulators Forum (AVAREF) established in 2006(AVAREF) established in 2006(AVAREF) established in 2006

ObjectivesObjectives To provide information to regulators of countries that are target for clinical trials

To promote communication/collaboration between NRAs and Ethics committees and To promote communication/collaboration between NRAs and Ethics committees and among regulators in the Region and others

To provide a resource of expert advise to regulators

To identify needs for expert support to NRAs

Modus OperandiModus Operandi One plenary meeting per year (2 to date) plus support activities between meetings;

joint WHO/HQ/AFRO activity

19 t i i l d NRA d N ti l Ethi C itt t ti 19 countries involved; NRA and National Ethics Committee representatives


AVAREF achievementsAVAREF achievements

An historical moment : ForAn historical moment : For the 1st time in Africa, regulators and ethics committee members fromcommittee members from Burkina Faso, The Gambia, Ghana, Ethiopia and Mali conducted an inspection ofconducted an inspection of Good Clinical Practice (GCP) inspection of phase II observer-blind, randomized, activeblind, randomized, active controlled clinical trial of meningococcal a conjugate vaccine at the Centre for Vaccine Development (CVD), Bamako, Mali; January, 2007


TrainingPlanning workshops for NRA strengthening

TrainingPlanning workshops for NRA strengthening g p g gg p g g

Twenty six countries Twenty six countries

The Gambia, Ghana, Nigeria, Ethiopia, Uganda and Kenya (Addis January 2005)Uganda and Kenya (Addis January 2005)

Senegal, Mali, Niger, Benin, Togo, RCA, Cameroon Burkina Faso and GuineaCameroon, Burkina Faso and Guinea(Ouagadougou May 2005)

Angola, Botswana, DRC, Malawi,Angola, Botswana, DRC, Malawi, Mozambique, Namibia, Rwanda, South Africa, Tanzania, Zambia and Zimbabwe (Gaborone Dec 2005)(Gaborone Dec 2005)


Training Workshops and coursesTraining Workshops and coursesg pg p “Evaluation of clinical trials”, Pretoria, March 2005

Regulatory Procedures for Evaluation of Vaccines (Addis Sept. 2005)g y ( p )

Regulatory forum on clinical evaluation of rotavirus vaccines (Botswana Dec. 2005)

Joint review of CTA of Conjugate Meningitis A vaccine (Banjul Jun 2006)Joint review of CTA of Conjugate Meningitis A vaccine (Banjul Jun 2006)

“Vaccine Regulation” (in French), M’bour, Senegal, March 2006

“Surveillance of AEFIs” (in French) in Senegal (2006), Tunis (2007) and (in English) Surveillance of AEFIs (in French) in Senegal (2006), Tunis (2007) and (in English) in Cape Town (RSA), 2006

“Authorization & Inspection of Clinical Trials” in French in Ouidah in December 2006 and in English in Harare in July 20072006, and in English in Harare in July 2007

“Good Clinical Practices” in English in Harare in July 2007

Joint Inspection of Men A Clinical Trials Bamako Mali Jan 2007** Joint Inspection of Men. A Clinical Trials, Bamako, Mali, Jan. 2007**

African trainees sent in 2006 to GTN courses on lot relase in Lyon, France, and on GMP in Seoul, Korea


New GTN coursesNew GTN courses

GMP inspections. Training Center: KFDA, KoreaGMP inspections. Training Center: KFDA, Korea

Testing of Hib conjugate vaccines. Training Center: NVI, The Netherlands

Authorization of Clinical Trials (Itinerant)

GCP inspection course (Itinerant)

Evaluation of Clinical data (Updated 2008) (Itinerant)

Lot Release (Updated 2007). Training Centers: AFSSAPS (in French) CDL Kasauli (in English)

Product Evaluation (under development)


2 New Regulatory Pathways2 New Regulatory Pathways2. New Regulatory Pathways2. New Regulatory Pathways

Collaboration with EMEA for the establishment of Scientific Opinion procedure (Art. 58)p p ( )

Procedure for expedited review of imported prequalified vaccines for use in immunizationprequalified vaccines for use in immunization programmes

C id i f ibili f bli hi l Considering feasibility of establishing mutual support mechanism between NRAs in Asia for the regulation of JE vaccinesJE vaccines


Procedure for expedited review of PQd vaccines

Procedure for expedited review of PQd vaccinesvaccinesvaccines

It is intended for countries that source their vaccines through UN It is intended for countries that source their vaccines through UN agencies, or who use the WHO prequalification as a basis for selection of vaccines for use in their national immunization programmes importing them through direct procurement It providesprogrammes, importing them through direct procurement. It provides guidance on how NRAs of such countries can expedite the regulatory review for such products.

Not intended to affect in any way post-approval activities in place in these countries

Countries intending to use the procedure should ensure that their national regulations contain provisions to allow to shorten the normal

l t lregulatory approval process.


Criteria for useCriteria for use

Scenario 1 Scenario 2Scenario 1 Scenario 2

For an expedited approval vaccines WHO-prequalified that are sourced through UN

For an expedited approval of WHO-prequalified vaccines that are procured directly.are sourced through UN

procurement agency.are procured directly.


Requirements for licensing vaccines from PQ sourcesRequirements for licensing vaccines from PQ sources

Scenario 1 Scenario 2

1. Same as in scenario 12. Same as in scenario 13. Same as in scenario 14 Same as in scenario 1in addition to

1. Check prequalification status2. Submit product samples, product

inserts, NRA lot release certificates from the country of origin a list of 4. Same as in scenario 1in addition to

ensure consistency with national tender specifications if different

5. Same as in scenario 1

from the country of origin, a list of countries where the product is licensed and marketed, and summary lot protocols of three final lots.

6. Same as in scenario 17. Same as in scenario 18. Same as in scenario 1

3. Visual inspection on samples4. Review protocols (check specifications),

labels, boxes and inserts against WHO model Ensure presence of VVMmodel. Ensure presence of VVM

5. Prepare report of compliance (non-compliance)

6. If compliant, issue Certificate of A lApproval

7. Inform manufacturer and WHO8. If novel vaccine with limited clinical data,

review of clinical data may be needed


review of clinical data may be needed

Outcome and timeframes for expedited review procedureOutcome and timeframes for expedited review procedure

Scenario 1 Scenario 21. Waiver of fees from countries is requested

2. Total timeframe for evaluation should not d 30 d l li i l d t d t

1. Same as in scenario 12. Same as in scenario 1. If country has

testing capabilities and vaccineexceed 30 days unless clinical data need to be reviewed, in which case timeframe is extended to 120 days

3 If info submitted by manufacturer is not

testing capabilities and vaccine samples will be tested as part of the registration process, 90 days instead of 30 will be the timeframe for completion

3. If info submitted by manufacturer is not complete, clock is halted awaiting. Completion.

4 Inform WHO that the procedure is being

of procedure, except when clinical data need to be reviewed (120 days)

3. Same as in scenario 14 Same as in scenario 1;4. Inform WHO that the procedure is being

adopted. WHO will keep NRA informed of updates regarding PQ status.

5. Procedure applies to vaccines used in NIP

4. Same as in scenario 1;5. Same as in scenario 16. Same as in scenario 1

pp

6. Countries should not stop use of PQ vaccines not yet registered in the country



Evaluating the acceptability of vaccine and vaccination ... · Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008. Process to strengthen NRAs The five step capacity building programme

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