An agency of the European Union

Three years of the Pharmacovigilance Risk Assessment Committee –

Where are we now?

June M Raine Chair, PRAC

MEB College Day Workshop 3rd June 2015

The Pharmacovigilance Risk Assessment Committee is the committee at the European medicines Agency that is responsible for assessing and monitoring safety issues for human medicines

Outline of presentation

• Why is there the need for a pharmacovigilance committee in EU?

• What has PRAC delivered via the new legislative public health tools in its first three years?

• Where next? What is still to be done to fully realise the potential of the new legislation to achieve excellence in public health protection?

Brussels, 19 July 2012

Why need for pharmacovigilance?

Duijnhoven et al PLoS March 2013

Patients studied prior to approval of new medicine For 200 new “standard” medicines between 2000 and 2010, median total no patients= 1708, for orphan drugs = 438 patients studied For 84 medicines for chronic use 79.8% met guidelines for 12 months (at least 100 participants)

Pharmacovigilance cycle

Better

characterised

risks of

medicine

Risk minimisation,

communication,

maintain favourable

benefit risk

Ongoing

evaluation of

benefit risk

Monitor risk

minimisation

effectiveness

Signal

detection in

real world use

New EU legislation in 2012

Clear legal framework for drug safety monitoring

Patient reporting of adverse drug reactions

Timely review of new safety issues

Risk management plans for all new medicines

Post-authorisation studies - regulatory oversight

Greater transparency

PRAC’s mandate

All aspects of the risk management of the use of medicinal products including the detection, assessment, minimisation and communication

relating to the risk of adverse reactions, having due regard to the therapeutic effect of

the medicinal product, the design and evaluation of post-authorisation safety studies

and pharmacovigilance audit

PRAC’s main goals

• Proactively investigating drug safety - continuous signal detection, filling knowledge gaps via post-authorisation studies

• Responding to safety and benefit risk issues – risk-proportionate decisions to rigorous timescales, effectiveness of risk minimisation

• Driving forward the new era in transparency - real time access to information on PRAC activities

• Increasing involvement of stakeholders - health professionals, patients and public

Pharmacoepidemiology

Marieke de Bruin

Stephen Evans

Pharmacovigilance

Hervé Le Louët

Signal detection

Lennart Waldenlind

Biologicals and vaccines

Brigitte Keller Stanislawski

Risk Communication

Jane Ahlqvist Rastad

European Commission experts

HCP and patient representatives

32 meetings

Over 150 protocol reviews

Over 1000 PSURs

33 safety referrals

Over 300

signals

Over 600 risk management

plans

PRAC monthly activities

Patient ADR reporting

Strengthened ADR reporting

* Number of ICSRs received in EudraVigilance before de-duplication

0

50.000

100.000

150.000

200.000

250.000

300.000

Pre Legislation02/07/11 - 01/07/12 After Legislation

02/07/12 - 01/07/13 After Legislation02/07/13 - 01/07/14

234.275

281.357 295.043

Additional monitoring list

Monthly review by PRAC of proposed additions to the list of new medicines for additional monitoring

Strengthened ADR reporting

EudraVigilance database provides common signal detection tools for all member states

>54% serious safety issues detected earlier if EV used in addition to other resources

Drug Safety 33(6) 475-487

Signal of medication error

Signal management review

PRAC’s Signal Management Review Team meets monthly under Dr Sabine Straus’ leadership to work on:

- Tools and processes

- Methodological guidance

- Signal detection methods

Implementing Regulation requires that “the Pharmacovigilance Risk Assessment Committee shall regularly review the methodology(ies) used and publish recommendations, as appropriate”

Pacurariu et al Drug Safety 15 Nov 2014

Signals & drug lifecycle

19

PRAC safety referrals

Referrals started and finalised

0

1

2

3

4

5

6

5 5 5

3 3 3

2 2

1 1 1 1 1

4

6

4 4

1 1

6

1

4

3

1

2

1

3

1 1 1 1

(Co) Rapporteurship per Member State

*3 procedures have multiple co-rapporteurs (SABA-HU, BE, CS, IT; RAS - UK, IT, SV, DE, NL, PT, SK, IE,

ES, Ambroxol/Bromhexine – PT, AT, BE)

Rapp

Co-Rapp

Rapporteurs for referrals

Review of all available data on known risk of VTE associated with combined hormonal contraceptives

Full information on risk of VTE to support decisions by women and their healthcare professionals

HCPs and women reminded to be watchful for symptoms and signs

Combined hormonal contraceptives VTE

Valproate & developmental disorders

Teratogenicity known since time of market authorisation

Assessment of latest evidence on risk of developmental disorder in infants following pregnancy exposure of mother

Strengthened warnings in product information to support decisions by women

Patient representatives involved in advising on risk minimisation measures

Ivabradine & cardiovascular risk

Small but significant increase of cardiovascular

death, MI and heart failure in SIGNIFY study in

ivabradine arm

Risk Minimisation Measures to include initiation heart

rate, dose, monitoring for atrial fibrillation &

stopping within 3 months if no benefit

Drug utilisation study to monitor RMM effectiveness

Proactive pharmacovigilance

Shift from reactive vigilance to proactive investigation of drug safety

To fill in gaps in knowledge, Risk Management Plans and PASS protocols are PRAC’s major priority

PRAC experts in pharmacoepidemiology provide specialist contributions on design and methodology

Better evidence on which to base regulatory decisions

Types of PASS reviewed by PRAC

Registries (prospective cohorts)

- Eg assess safety profile, health outcomes in clinical use, consider existing infrastructure consider comparator

Database studies

- Eg risk characterisation, investigation of targeted AEs

Drug utilisation studies

Eg to assess effectiveness of risk minimisation measures or help plan PAS

Special populations

- Pregnancy registries, paediatrics, elderly

Medication errors

- Human factors studies

Strontium ranelate

PASS imposed after PSUR raised concerns about cardiovascular safety and further in-depth evaluation of benefit risks under Article 20 referral MAH`s proposal: descriptive study using retrospective healthcare databases Main methodological issues related to ability of proposed algorithms to extract reliable information on variables and endpoints from proposed data sources

Isotretinoin pregnancy prevention

Driving forward transparency

Information

technology

Innovative

science

Innovative

methodologies

Involvement

of patients

Impact

evaluation

PRAC’s work moving forward

Innovative science

Using pharmacogenomics to define populations at risk of ADRs

Innovative methodologies

Incorporating new methodologies in signal detection, benefit risk evaluation and risk communication based on research and best evidence

Impact evaluation

Information technology

Innovative Medicines Initiative WEB-RADR project

Development of a mobile app for

–ADR reporting

–Provision of information to users

Evaluation of using social media data to identify ADRs

Involving patients & public

Interaction with patient and health professional organisations so far during formal reviews

Input to setting goals for RMMs, reviewing thresholds and decisions on effectiveness of RMMs

Opportunity of public hearings to be introduced later in 2015

Reflections on 3 years of PRAC

Real-time signal detection and signal prioritisation every month at PRAC

Rapid action to manage risk with binding outcomes

Benefit risk monitoring throughout a medicine’s life cycle in clinical use

New era of transparency and openness in place

Current initiatives based on best evidence, effectiveness evaluation, and stakeholder engagement

PRAC’s goal is measurable impact of what we do: demonstrable excellence in public health protection

Hartelijk dank!