evaluating the acceptability of vaccine and vaccination ... · dr. nora dellepiane, scientist...
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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
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)
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
Recommended regulatory functions d f i WHOand source of vaccines. WHO
support to strengthen regulatory pp g g yfunctions
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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)
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
Country Status: country assessment of vaccine regulatory system conducted , September 1997
NRA assessments conducted
NRA assessments completed
& planned
Not yet conducted
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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)
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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)
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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.
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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.
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008
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
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS |July 2008