# Presentation: 710677

## European Regulatory Authority (EMEA) experience

- NIH, Bethesda, April 10-11, 2007

**European Regulatory Authority (EMEA) experience**

- Xavier Kurz
- Pharmacovigilance and Post-Authorisation Safety & Efficacy of Medicines
- European Medicines Agency, London

## Outline

- The EU Risk Management System
- Specific aspects of vaccines
- Data sources for vaccine surveillance
- Example: avian influenza vaccines (prepandemic and pandemic)

## The European Medicines Agency

**The European Medicines Agency**

- Was created in 1995 – based in London
- Manages the **Centralised Procedure**
- Generates Scientific Opinions
- Co-ordinates the existing scientific resources in the EU for the evaluation, supervision and pharmacovigilance of medicinal products
- Relies on the scientific expertise and competences of some 4,000 European experts made available by the national competent authorities

- www.emea.europa.eu

## The Centralised Authorisation Procedure (CAP) 

- Single application, evaluation and Marketing Authorisation for whole EU
- Evaluation by Committee for Human Medicinal Products (CHMP)
- Maximum time limit                                                               210 days evaluation for CHMP Opinion
-              Commission Decision (MA)
- Common product information (22 languages)
- Access to entire EU Market

## The Centralised Authorisation Procedure (CAP) 

- Biotechnology-derived medicinal products (incl. vaccines)
- New active substances (HIV/AIDS, cancer, diabetes, neurodegenerative disorders - *May 2008: viral diseases, autoimmune diseases)*
- Orphan medicinal products intended for the treatment of rare diseases
- Optional
- New active substances
- Significant innovation (therapeutic, scientific, technical or in the interest of patient in any other respect )
- Generics of centralised products

*... dedicated to innovative products*

**The Centralised Authorisation Procedure (CAP)*** *

## Vaccines authorised through the Centralised procedure (04/2007)

- Vaccines authorised through the Centralised procedure (04/2007)

## Avian influenza vaccines

- Positive CHMP Opinion:
- 	Daronrix		Pandemic use
- 	Focetria		Pandemic use
- Under evaluation
- 	4 vaccines for pandemic use
- 	2 vaccines for prepandemic use

## +

**Submission**

**CHMP **
**decision**

**European**
**Commission**
**decision**

- 210 days

- 14 days

**Presubmission meetings**
**Scientific advice**
**Protocol assistance**
**Orphan designation**

**Pharmacovigilance**
**Risk Management**
**Post Commitments**
**Post-A. Procedures**

**Post-authorisation **
**phase**

**+**

- Vaccines: same legislation and procedures as other medicinal products

## Situations where a Risk Management Plan is required

**  **New marketing authorisation
- New active substance
- Biosimilar product
- Generic where safety issue with innovator
-   Significant changes to Marketing Authorisation
-   On request from the Competent Authority
-   On company initiative e.g. safety issue with a marketed
-     medicine

## Part I

- Safety Specification
- Pharmacovigilance Plan
- Part II
- Evaluation of need for risk minimisation measures, if so
- Risk minimisation plan

- Risk Management Plan

## Safety Specification

- At the end of the Specification, there should be a summary of :
-  important identified risks of a drug
-  important potential risks of a drug
-  important missing information

- Summary of what is known and not known about the safety of a medicinal product at the time of authorisation.

## Pharmacovigilance Plan

- Action plan to address each issue identified in the safety specification
- For products for which no special concerns have arisen: routine pharmacovigilance may be sufficient (ADR reporting, signal detection, PSUR,...)
- For products with potential or identified safety concerns, additional pharmacovigilance activities to be considered, e.g.
-  active surveillance
-  intensive monitoring
-  PhEpi studies

## Specific aspects of vaccine surveillance

- many vaccines are nationally-authorised
- immunisation programmes generally regulated by authorities in charge of public health protection
- immunisation schedules may vary across MS
- different methods of vaccine surveillance

## Vaccine Working Group (VWG)

- To provide recommendations to CHMP on all matters relating directly or indirectly to vaccines
- evaluation of new applications and post-authorisation issues
- scientific advice and guidelines
- support to the conduct of vaccine-specific epidemiological studies

- European Centre for Disease Prevention and Control (ECDC)

- Established in 2004 in Stockholm, Sweden
- Created to help strengthen Europe’s defences against infectious diseases
- Works in partnership with national health protection bodies across Europe to strengthen and develop disease surveillance and early warning systems

## European networks on vaccines and immunisation

**V****accine ****E****uropean ****N****ew ****I****ntegrated ****C****ollaboration ****E****ffort** (**VENICE**)
- Collaboration and partnership on immunisation policies

**EUVAC.NET**
- Surveillance community network for vaccine preventable infectious diseases namely: measles, rubella, pertussis, mumps and varicella
- standardised surveillance methodologies
- disease epidemiology
- laboratory surveillance methods (e.g. sentinel physician/ paediatrician networks)

**E****uropean ****S****ero-****E****pidemiology ****N****etwork (ESEN)**

- Harmonisation of methodologies for sera collection and testing

## European Vaccine Manufacturers (EVM)

- Producer of approximately 80% of vaccines used worldwide
-    (EVM website)
- Mission: improved vaccine protection and coverage in the interest of individual and community public health
- Membership
- Baxter: Austria
- Berna A Crucell Company: Switzerland and Spain
- GlaxoSmithKline Biologicals: Belgium
- Novartis Vaccines: Italy and Germany
- Sanofi Pasteur: France
- Sanofi Pasteur MSD: France
- Solvay Pharmaceuticals: The Netherlands
- Wyeth Vaccines: Belgium

## Other collaborations

- World Health Organisation
- Brighton Collaboration

## Data Sources

- Spontaneous reports: Eudravigilance Data Warehouse

## Active “surveillance” via record linkage systems
Linkage of clinical records with immunisation records 
Systems established in UK ( General Practice Research Database and others using hospital databases), also Denmark, Finlandand Italy

 Amenable to analytical epidemiological studies
hypothesis testing
cohort studies
self-controlled case-only analysis  

- Linkage of clinical records with immunisation records
- Systems established in UK ( General Practice Research Database and others using hospital databases), also Denmark, Finlandand Italy
-  Amenable to analytical epidemiological studies
- hypothesis testing
- cohort studies
- self-controlled case-only analysis

## Record linkage databases

-  THIN (UK) (integral database): 2.4 million patients
-  IMS Health Mediplus – UK
-  IMS Health Mediplus – DE
-  Funen Country (DK) (Record linkage): 465,000 patients
-  Friuli-Vennezia-Giulia (IT) (Record linkage): 1.2 million patients
-  Umbria (IT) (Record linkage): 850,000 patients
-  PHARMA (NL) (Record linkage): 500,000 patients
-  MEMO (UK) (Record linkage): 400,000 patients
-  BIFAP (Spain) (Integral database), feasibility study: 1 million patients
-  others ...

- Examples of databases in the EU

## General issues with some databases across EU

-  own coding system
-  unequal data quality
-  unequal completeness of data/coding
-  inadequate sample size for rare events
-  missing data on confounders/effect modifiers
-  access for research

## Concept

- Submission and approval of a Core pandemic dossier in inter-pandemic period  authorisation of a “mock-up vaccine” in 150 days
-  limited immunogenicity and safety data pre-authorisation
-  no effectiveness data
- Fast track approval of the pandemic vaccine in 3 days
- At the time of licensure: post-approval commitments for protocols to ensure that immunogenicity, effectiveness and safety of final pandemic vaccine are adequately documented during use in the field (protocols already in place)

- Example of proactive vaccine surveillance: Core Pharmacovigilance Plan for Pandemic Influenza Vaccines

- Core Pharmacovigilance plan

## Core Pharmacovigilance Plan for Pandemic Influenza Vaccines

- Developed through a collaboration of VWP, PhVWP and EVM
- Approved by CHMP in November 2006
- Clear distinction made between
- Pre-pandemic period: routine pharmacovigilance
- Pandemic period: additional pharmacovigilance activities

## 1. Spontaneous reports
Reporting prioritised for
Fatal or life-threatening adverse reactions
Serious unexpected adverse reactions
AESI: neuritis, convulsions, severe allergic reactions, syncope, encephalitis, thrombocytopenia, vasculitis, GBS, Bell’s palsy
Spontaneous reporting from patients
to be recorded
analysed and reported separately
Expedited reporting
preferably within 7 days for fatal and life-threatening adverse reactions and for AESI
Recommendations for signal detection

- Reporting prioritised for
- Fatal or life-threatening adverse reactions
- Serious unexpected adverse reactions
- AESI: neuritis, convulsions, severe allergic reactions, syncope, encephalitis, thrombocytopenia, vasculitis, GBS, Bell’s palsy
- Spontaneous reporting from patients
- to be recorded
- analysed and reported separately
- Expedited reporting
- preferably within 7 days for fatal and life-threatening adverse reactions and for AESI
- Recommendations for signal detection

- Core Pharmacovigilance Plan for Pandemic Influenza Vaccines (2)

## Core Pharmacovigilance Plan for Pandemic Influenza Vaccines (3)

- _2. Periodic Safety Update Reports_
- PSUR cycle replaced during pandemic with two-weekly reports of aggregated data on fatal and life-threatening ADRs, AESI, serious unexpected ADRs, reports by age groups and in pregnant women, patients’ reports
- Short summary highlighting areas of concern with timelines for full signal evaluation report
- Ad-Hoc report if serious safety concern arises
- Vaccine distribution report
- EU MS for the reporting period, by batch
- EU MS cumulatively
- rest of world

## Core Pharmacovigilance Plan for Pandemic Influenza Vaccines (4)

- _3. Additional pharmacovigilance activities_
- Prospective cohort study for each vaccine
- Cohorts  to be identified in the pre-pandemic period according to national plans
- Solicited events
- Sample size of 9,000 subjects, stratified by age groups
- 		(6-23 m., 2-7 y., 8-17 y., 18-60 y., > 60 y.)
- 6-month follow-up
- Dynamic database - rapid communication of data
- Only in some countries according to feasibility criteria
- Common protocol proposed by EVM
- Specific activities for rare events (eg. network of specialists for GBS)

## Core Pharmacovigilance Plan for Pre-pandemic avian influenza vaccines

- Vaccines to be used in pre-pandemic _and_ pandemic periods
- More stringent requirements for authorisation
- 	Safety database before authorisation
- 3,000 adults from 18 to 60 years
- 30 to 300 subjects for specified age groups (infants, adolescents, adults >60 years)
- 300 subjects from specified risk groups (immunocompromised patients, chronically ill patients)

## Core Pharmacovigilance Plan for Pre-pandemic avian influenza vaccines

- Ongoing discussions
- Immunogenicity and effectiveness
- Pv plan in pre-pandemic _and_ pandemic periods
- AESI, signal detection methods
- Need for specific periodic safety update reports (format/periodicity)
- Expansion of safety database post-marketing:
- Groups of subjects to be studied
- Minimum requirements
- Tansition to pandemic period

## Same regulatory requirements for vaccines as for other medicinal products
Increasing number of centrally-authorised vaccines (same regulation throughout EU)
Use of vaccines and immunisation schedule are the responsibility of national competent authorities
Harmonisation of surveillance methods is an important step in enhancing vaccine safety in the EU
Relatively small number of vaccine manufacturers may be an asset to establish partnership and effective surveillance programmes 

- Increasing number of centrally-authorised vaccines (same regulation throughout EU)
- Use of vaccines and immunisation schedule are the responsibility of national competent authorities
- Harmonisation of surveillance methods is an important step in enhancing vaccine safety in the EU
- Relatively small number of vaccine manufacturers may be an asset to establish partnership and effective surveillance programmes

- Conclusion

## 
Passive reporting systems are essential for identifying rare AEs and hypothesis generation 
Active surveillance through record linkage systems allows rapid and powerful hypothesis testing 
Self controlled case series is a major methodological  advance with potential for wider application in risk assessment

RMP for pandemic and prepandemic influenza vaccines may represent a paradigm for post-authorisation safety surveillance

- Passive reporting systems are essential for identifying rare AEs and hypothesis generation
- Active surveillance through record linkage systems allows rapid and powerful hypothesis testing
- Self controlled case series is a major methodological  advance with potential for wider application in risk assessment
- RMP for pandemic and prepandemic influenza vaccines may represent a paradigm for post-authorisation safety surveillance

- Conclusions (2)