Drug Regulatory Systems Strengthening (RSS)

WHO Technical Briefing Seminar on Essential Medicines and Health Products

31 October 2013WHO Headquarters, Geneva, Salle M 505

Dr Claudia P Alfonso

Drug Regulatory Systems Strengthening (RSS)

WHO Technical Briefing Seminar on Essential Medicines and Health Products

31 October 2013WHO Headquarters, Geneva, Salle M 505

Dr Claudia P Alfonso

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OutlineOutlineGlobal overview of vaccine production and immunization

The WHO Regulatory Systems Strengthening (RSS) Programme and the five-step capacity building model

Assessments of national regulatory authorities (NRA) and harmonized tool development

NRA Institutional Development Plans (IDP)

Link between WHO Prequalification and NRA assessment

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Global initiatives: coalition to support immunizationGlobal initiatives: coalition to support immunization

WHO Expert Committee on Biological Standardization (ECBS)

Smallpox eradication

Polio eradication

Measles elimination

Global Immunization Vaccine Strategy

Decade of vaccines (DoV)

Global Alliance for Vaccine & Immunization (GAVI)

UN Millennium Development Goals (MDGs)

WHO reform

WHOVaccine prequalification (PQ)

Universal Child Immunization (UCI) -1990

1947

1959 1980

19881987

1990

1999

2000

2006

2000

20102011

20202015

2015IFFImInternational Finance Facility

For Immunization

2006

Expanded Programme on Immunization - 1974

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Global challengesGlobal challenges1. Demand for more vaccines

2. Raise of public awareness about vaccines

3. New standards promoted by WHO

4. Anticipate new needs for regulation vaccines

5. Quality control systems established in countries need increased investment to be sustained

6. Domestic production not consistent in volume and quality has difficulty to meet cGMP standards

7. Shift in vaccine market and increase segmentation

1. New initiatives and global coalition efforts: GAVI, DoV, influenza, polio eradication, measles immunization, introduction of new vaccines, others

2. Public and media expectations increased through media, internet and social networks

3. Vaccine science requires new standards

4. Vaccines needs thorough regulations to address specificity

5. QC is more complex and expensive

6. Volume increasing and cGMP standards raising too

7. EPI vaccines are traditionally produced by developing countries while new vaccines are produced by developed countries.

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Vaccine producing1990 :63 countries1997 :52 countries

2012 :44 countries

Vaccine demand increases while number of producing countries decreases

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Major vaccine producing countries 1997-2012146 vaccine manufacturers, 95% global production in 16 countries

Brazil

ChinaUSA

Senegal

Indonesia

India

Russia

France

Belgium

Italy

Canada

Japan

Korea

Denmark

Cuba

Developing countries

Bulgaria

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12 Developing countries with emerging vaccine production or high potential

to account for 80-70% of the global production

Brazil

China

Mexico Senegal

Indonesia

IndiaViet Nam

Russia

IranEgypt

Cuba

Largest volume production

Bulgaria

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UNICEF purchases 40% of global volume of vaccine doses mainly EPI vaccines which represents only 5% of market value

40%

5%

Global Volume of Doses Global Value of Doses

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Vaccines are different from drugsVaccines are different from drugs

Biological products (Variation)

Heat sensitive (Cold chain)

Sensitive to light and freezing

Limited shelf life

Mandated by public health programme (EPI or NIP)

Targeted to healthy children and mothers

Given for prevention - recipient cannot judge treatment

Pennies per dose, new vaccines are more expensive

Limited number of products and manufacturers

Given once or only a few times

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WHO Prequalification PrincipalsWHO Prequalification Principals

Reliance on NRAs

General understanding of the product – presentations offered – production process – quality control methods – quality system in place – clinical data relevant to the target population

Assurance of production consistency through compliance with GMP

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WHO DEFINITION OF VACCINES OF ASSURED QUALITY

WHO DEFINITION OF VACCINES OF ASSURED QUALITY

The National Regulatory Authority (NRA) is able to regulate independently vaccines against standards of quality, safety and efficacy (QSE) in accordance with the WHO recommended functions defined by WHO, and

There are no unresolved confirmed reports of quality-related problems.

Ensuring vaccine quality for use in national immunization programmes: concept evolution

AssessmentTraining Technical support

MonitoringProgress

ImpactBenchmarking

Regulatory Systems Strengthening 60 functional NRAs, 80% of all producing countries, 97% vaccines of assured quality

1996 1997 1997 1998 2004 2011

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WHO NRA Five-Step Capacity Building Model

WHO NRA Five-Step Capacity Building Model

Bench Marking

Development of NRA assessment

tool

Assessment of NRA

Development of Institutional

Development Plan (IDP)

Providing technical support, Training/Learning

, networking,

Monitoring progress and

impact

Fu

nc

tio

na

l NR

A

1 2 3 4 5

Revised indicators (2-3 years)

Re-assessmentEvery 2-5 years

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Laboratory access

Laboratory access

Regulatory inspections

Regulatory inspections

Authorization clinical trials (Ethical review process, compliance against GLP, GMP, GCP)

Authorization clinical trials (Ethical review process, compliance against GLP, GMP, GCP)

Pre-marketing phasePre-marketing phase Post Marketing phasePost Marketing phase

Post marketingAEFIsurveillance

Post marketingAEFIsurveillance

Lot releaseLot release

Market distribution

QualityQuality

SafetySafety

EfficacyEfficacy

ProductEvaluation

ProductEvaluation

Licensingfacility

Licensingfacility

ApplicationApplication

Licensing/Registration=evaluation process

Applicants Dossier(manufacturer ordistributor)

Applicants Dossier(manufacturer ordistributor)

Marketing AuthorizationMarketing Authorization

Vaccine regulatory processVaccine regulatory process

InspectionsInspections

testing

testing

monitoring

Regulatory function to implement

Vaccine source

UN agency Procure Produce

Regulatory system (RS) √ √ √

Marketing authorization and licensing (MA) √ √ √

Pharmaco-vigilance (PV) including AEFI monitoring

√ √ √

Lot release (LR) Undertaken by WHO on behalf of UN agencies or producing countries

√ √

Laboratory access (LA) √ √

Regulatory inspections (RI)

Undertaken by the

producing country

√

Oversight or clinical trials (CT) √

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Chronology of indicators in the WHO NRA assessment tool for vaccines

NRA ASSESSMENT TOOLS: 1999, 2001, 2002, 2004 & 2007Progress of the number of total & critical indicators and sub-indicators

54 53 51

32 38

45

173164

173

183 181

128

616354

4* 4*

88**

70**

0

20

40

60

80

100

120

140

160

180

200

1999 2001 2002 2004 2007 2011

NRA assessment tools

Total indicators Total critical indicators Total sub-indicators Total critical sub-indicators

*Critical but not for Pre-qualification (PQ)**Critical as required for vaccine PQ

18 |National Regulatory System, Status of vaccine indicators

Harmonized tool: regulatory functionsHarmonized tool: regulatory functions

1. NATIONAL REGULATORY SYSTEM2. REGISTRATION AND MARKETING AUTHORIZATION3. LICENSING ACTIVITIES4. POST-MARKETING SURVEILLANCE (+ LOT RELEASE FUNCTION)5. OVERSIGHT OF CLINICAL TRIALS6. INSPECTIONS AND ENFORCEMENT ACTIVITIES7. LABORATORY ACCESS AND TESTING8. VIGILANCE AND RISK MANAGEMENT9. CONTROL OF PROMOTION AND ADVERTISING10. CONTROL OF NARCOTICS, PSYCHOTROPIC SUBSTANCES AND PRECURSORS11. PHARMACEUTICAL PERSONNEL

19 |National Regulatory System, Status of vaccine indicators

PAHO TOOL MEDICINES TOOL MEDICAL DEVICES & DIAGNOSTICS

VACCINES TOOL WHO-PAHO HARMONIZED TOOL

1. SISTEMA NACIONAL DE REGULACIÓN

Module 2 - NATIONAL REGULATORY SYSTEM

NRS: NATIONAL REGULATORY SYSTEM

RS: NATIONAL REGULATORY SYSTEM

1.NATIONAL REGULATORY SYSTEM 

2.  AUTORIDAD REGULADORA NACIONAL

Module 3 - NATIONAL REGULATORY AUTHORITY

3. REGISTRO SANITARIO Module 4 - MARKETING AUTHORIZATION

MA: MARKETING AUTHORIZATION (MA) FOR MEDICAL DEVICES AND DIAGNOSTICS

FUNCTION 1: MARKETING AUTHORIZATION AND LICENSING ACTIVITIES

2.REGISTRATION AND MARKETING AUTHORIZATION

4. LICENCIAMIENTO DE PRODUCTORES

Module 5 - LICENSING OF MANUFACTURERS

LI: LICENSING OF MANUFACTURERS, IMPORTERS, DISTRIBUTERS AND RETAILERS OF MEDICAL DEVICES AND DIAGNOSTICS

3.LICENSING ACTIVITIES

Module 6 - LICENSING OF IMPORTERS, EXPORTERS, WHOLESALERS AND DISTRIBUTORS

Module 7 - LICENSING OF PHARMACIES AND RETAIL OUTLETS

 

Module 8 - REGISTRATION OF PHARMACY PERSONNEL

  11.PHARMACEUTICAL PERSONNEL (HEALTH/REGULATORY??)

Regulatory functions: former and harmonized tool

20 |National Regulatory System, Status of vaccine indicators

PAHO TOOL MEDICINES TOOL MEDICAL DEVICES & DIAGNOSTICS

VACCINES TOOL WHO-PAHO HARMONIZED TOOL

5.   VIGILANCIA DEL MERCADO Module 9 - POST-MARKETING SURVEILLANCE AND CONTROLS

PMS: POST- MARKETING SURVEILLANCE

FUNCTION 2: POST-MARKETING ACTIVITIES INCLUDING SURVEILLANCE OF ADVERSE EVENTS FOLLOWING IMMUNIZATION (AEFI)

4.POST-MARKETING SURVEILLANCE (includes vaccine lot release function)

6.  FARMACOVIGILANCIA Module 11 - PHARMACOVIGILANCE

VR: VIGILANCE AD RISK MANAGEMENT ACTIVITIES ON MEDICAL DEVICES AND DIAGNOSTICS

8.VIGILANCE AND RISK MANAGEMENT

Module 10 - CONTROL OF MEDICINES PROMOTION AND ADVERTISING

PR: CONTROL OF PROMOTION AND ADVERTISSEMENT FOR HEALTH PRODUCTS

9.CONTROL OF PROMOTION AND ADVERTISING

7. CONTROL DE ENSAYOS CLÍNICOS

Module 12 - CLINICAL TRIALS CT: OVERSIGHT OF CLINICAL TRIALS on IVDs and MD

FUNCTION 6: REGULATORY OVERSIGHT OF CLINICAL TRIALS

5.OVERSIGHT OF CLINICAL TRIALS

8. INSPECCIONES REGULADORAS Y ACTIVIDADES DE FISCALIZACION

Module 13 - REGULATORY INSPECTIONS AND ENFORCEMENT ACTIVITIES

IE: INSPECTIONS AND ENFORCEMENT ACTIVITIES

FUNCTION 5: REGULATORY INSPECTIONS

6.INSPECTIONS AND ENFORCEMENT ACTIVITIES

9. LABORATORIO NACIONAL DE CONTROL DE CALIDAD

Module 14 - QUALITY CONTROL LABORATORY

LABORATORY ACCESS AND TESTING

FUNCTION 4: LABORATORY ACCESS

7.LABORATORY ACCESS AND TESTING

FUNCTION 3: NRA LOT RELEASE

  Module 15 - CONTROL OF NARCOTICS, PSYCHOTROPIC SUBSTANCES AND PRECURSORS

  10.CONTROL OF NARCOTICS, PSYCHOTROPIC SUBSTANCES AND PRECURSORS

Module 16 - INTERNATIONAL COOPERATION AND HARMONIZATION

   

Regulatory functions: former and harmonized tool

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2013 NRA STATUS PER WHO REGIONGrand Total Not functional Functional

46 41 5 AFR

35 31 4 AMR

22 15 7 EMR

53 20 33 EUR

11 7 4 SEAR

27 20 7 WPR

194 134 60 Grand Total

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GRACIASMERCI