Pharmacovigilance in real life may 12

Pharmacovigilance in
Real Life
An Industry Perspective

Barry Arnold
EU Qualified Person for Pharmacovigilance
AstraZeneca

Content of presentation

• Why undertake pharmacovigilance?
• Pharmacovigilance processes
• Impact of new EU legislation

PV in real life | May 2012 Global Medicines Development | Chief Medical Office

Why Undertake
Pharmacovigilance?

Historical Milestones

……. 50 years ago


Milestones
1961 Thalidomide: phocomelia
1962 High dose isoprenaline: asthma deaths
1970 High dose oestrogen oral contraceptives: thromboembolic disease
1971 Diethylstilboestrol: vaginal carcinoma in daughters
1974 Pertussis vaccine: encephalopathy
1975 Practolol: oculomucocutaneous syndrome
1979 Triazolam (Halcion): psychiatric symptoms
1982 Benoxaprofen (Opren): hepatotoxicity & photosensitivity in elderly
patients
1993 Fialuridine: hepatotoxicity
1993 Sorivudine: fatal neutropenia (interaction with 5FU)

1996 3rd generation oral contraceptives: venous thromboembolism
1997 Troglitazone (Rezulin): hepatoxicity


Milestones cont‟d

1998 Seldane (terfenadine) Posicor (mibefradil)
Duract (bromphenac) „Fen-phen‟ (fenfluramine/phentermine)
1999 Hismanal (astemizole) Raxar (grepafloxacin
2000 Prepulsid (cisapride) Lotronex (alosetron)
2001 Baycol (cerivastatin)
2004 Vioxx (rofecoxib)
2005 Tysabri (natalizumab) Bextra (valdecoxib)
2007 Avandia (rosiglitazone)
2008/09 Selective Serotonin Reuptake Inhibitors
2008/12 Proton Pump Inhibitors
2012 Implementation of new EU legislation


Why undertake pharmacovigilance?

• To quickly identify, evaluate and communicate
potential risks to patients
- Optimise prescribing information & patient information
- Comply with regulations, and satisfy regulators
- Reduce the risk of product liability


“Show me a drug without side-
effects and I shall show you a drug
that does not work”
Dunlop


The Pharmacovigilance
Process

What is Pharmacovigilance?

• The science & activities relating to the detection,
assessment, understanding and prevention of adverse
events or any other drug-related problems (WHO).

• The ongoing process by which we conduct a
systematic evaluation of safety data in order to
anticipate, identify, respond to and communicate about
safety issues throughout the life-cycle of
pharmaceutical products (Anon).


Pharmacovigilance has no boundaries


AstraZeneca Patient Safety
Executive Director
Global Development
Chief Medical Officer VP, Clinical Development

QPPV VP, Patient Safety

Epidemiology

Processes & Standards Team Safety Science

USA UK Sweden

Tata Consulting
Services
Safety Surveillance Support


Role of AstraZeneca Patient Safety

• Provide integrated strategic safety expertise to clinical
development programmes
• Conduct active pharmacovigilance with rapid
identification and analysis of safety signals; define the
safety profile of AZ products and drive patient risk
management
• Deliver high quality product safety information
throughout the product life cycle
• Ensure regulatory compliance


EU Qualified Person for Pharmacovigilance

• QPPV responsible for:
- Collection and collation of all suspected ADRs; to be
accessible at least at one point within the EU
- Preparation of expedited and periodic safety reports, and
reports on post-authorisation safety studies
- Ongoing pharmacovigilance evaluation
- Responding to requests for information from regulatory
authorities
- Provision of additional information upon request from
Competent Authorities relevant to evaluation of benefit-
risk
- Notifying changes to benefit-risk profile
- QC/QA of the pharmacovigilance system

Pharmacovigilance Process

Healthcare Professional
Consumer
Lawyer
Regulatory Authority

Literature Regulatory Safety
Spontaneous Reports Reports Updates
Reports

Database Data Review
Data In Output Action
Entry & Evaluation
Study &
PMS
Data
Follow-up Data Response to Signal
Regulatory Enquiry Generation
Reports


AstraZeneca Case Handling Process

Queries Queries

Reporter/ Data Entry Site
AZ staff
Investigator JASPER
MC/CRO

Marketing Companies

Regulatory Authorities

Expedited ADR Reports

• Clinical development products
- 7 days: fatal/life-threatening unexpected ADRs
- 15 days: other serious unexpected ADRs
• Marketed products
- 15 days: serious ADRs
• All products: other important safety information to be
submitted without delay
• AZ generates reports for all serious ADRs submitted
individually (selected by computer algorithm)


PSURs

• Provided to EU regulatory authorities:
- 6 monthly for first 2 years after marketing
- Annually for subsequent 2 years
- Thereafter at 3 yearly intervals
• Presentation, analysis and evaluation of new or
changing safety data received during period of PSUR
• Reassure all relevant regulatory authorities that:
- Safety surveillance activities are appropriate
- Core Data Sheet (with any proposed amendments)
accurately reflects the benefit-risk profile of the product
and its safe use in clinical practice


Safety Surveillance

• Proactive detection of safety signals
- Optimises protection of patients
- Meets regulatory expectations
• Safety signals arise from numerous sources e.g.
individual case reports, published literature, clinical
studies, regulatory authorities, etc
• Manual review supported by automated quantitative
signal detection (disproportionality analyses) of in-
house and external safety databases
• Cross-functional peer review process for signal
evaluation


Risk Management Plans
• Risk Management Plan: A plan identifying the risks
associated with a medicinal product, methods to
further clarify the safety profile of a product, and ways
to minimise risk to individual patients in clinical use
 Safety Specification

 Pharmacovigilance Plans
 Risk Minimisation Activities
• Each RMP should be unique for the product under
consideration


Risk management

A risk that is recognised, quantified and
publicised is a risk accepted
A lesser risk, as a surprise can kill a drug

Anon


Risk Management Plans

Could these products have avoided
withdrawal if they had effective risk
management plans at launch?

• Alosetron • Sibutramine
• Cisapride • Soruvidine
• Cerivastatin • Terfenadine
• Felbamate • Troglitazone
• Sertindole


Impact of EU
Pharmacovigilance
Legislation

Rationale for new legislation

In light of experience and following an assessment
made of the EU pharmacovigilance system……made
by the Commission, it has become clear that new
measures are necessary to improve how the EU rules
operate on the pharmacovigilance of medicinal
products.
Today’s proposals seek to change the existing EU
legislation on pharmacovigilance (…). They aim at
strengthening and rationalizing the EU
pharmacovigilance system, with the overall objectives
of better protecting public health, ensuring proper
functioning of the internal market and simplifying the
current procedures.


EU Pharmacovigilance Legislation

• Objectives
 Strengthen & rationalise EU pharmacovigilance system
 Greater transparency

• Published in Official Journal of EU (31 December 2010)
 Regulation (EU) 1235/2010, amending Regulation (EC)
726/2004
 Directive 2010/84/EU, amending Directive 2001/83/EC
 New provisions will apply from July 2012/January 2013/2015

• Further details to be provided during 2012
 European Commission ‘Implementing Regulation’
 European Medicines Agency guidelines (Good Vigilance
Practice & Post-Authorisation Efficacy Studies)


Implementing Regulation

1. Pharmacovigilance system master file
2. Quality system for performance of PV activities
3. Monitoring of data in EudraVigilance
4. Use of terminology
5. Transmission of suspected adverse reactions
6. Risk management plans
7. Periodic safety update reports
8. Post-authorisation safety studies
9. Final provisions
Annexes I-III


Good Vigilance Practice Guideline

• Principles to be applicable to MAH PV systems globally
• To apply across all member states
 Any deviation from the guideline to be fully justified
• 15 modules + 5 annexes: will be several hundred
pages long!
• Draft guidelines being issued in ‘waves’ for public
consultation
- Wave I – February 2012; 8 weeks consultation period
- Wave II – to be determined


Principles for Good Vigilance Practice

• Higher management to lead implementation of the quality
system and motivation for all staff in relation to quality
objectives
• All persons within the organisation to be involved in and
support the pharmacovigilance system on the basis of task
ownership and responsibility; all persons should engage in
continuous quality improvement
• Resources and tasks to be organised to support proactive,
risk-proportionate, continuous and integrated conduct of
pharmacovigilance
• All available evidence on benefit-risk of medicinal products
should be sought; all relevant aspects, which could impact
on benefit-risk and the use of a product, should be
considered for decision-making

Summary of the Pharmacovigilance System

• Each MAA to include the following information:
- Proof that the applicant has the services of a QPPV
- Member State where the QPPV resides & works
- Contact details for the QPPV
- Statement signed by the applicant to the effect that the
applicant has the necessary means to fulfill its
pharmacovigilance responsibilities
- Location of the pharmacovigilance system master file
• Amendment to this information will require a ‘variation’


Supervisory authority

• The ‘supervisory authority’ for pharmacovigilance will
be the competent authority of the Member State in
which the MAH pharmacovigilance system master file
is located
• Responsible for verifying on behalf of the Community
that the MAH meets pharmacovigilance requirements
i.e. through PV inspections


European Medicines Web-Portal

• EMA to establish European medicines web-portal
increase transparency of pharmacovigilance issues
• Public access to:
 List of CHMP, CMDh & PRAC members
 PRAC meeting agendas & minutes
 List of products subject to ‘additional monitoring’
 List of locations of MAH master files & contact information for
pharmacovigilance enquiries
 PSUR reference dates, frequency of submission, and PSUR
assessment reports (conclusions)
 Summaries of RMPs
 PASS protocols & abstracts of results
 Information on ‘urgent’ EU procedures


Impact on workload

• Increased workload associated with the following:
- Quality system
- PV System Master File
- Data management
- Signal management
- ICSR reporting
- Assessment of off-label use
- Risk management plans
- Effectiveness of risk minimisation
- Post-authorisation studies
• Periodic reports: depends what type of product the company
markets
• Increased transparency: difficult to predict

Future Expectations

• Changes to regulatory requirements
- EU legislation: Strengthening, transparency and rationalisation of
pharmacovigilance requirements
- Clinical Trials Directive: strengthen or rationalise?
• Increased involvement of patients in pharmacovigilance
- Direct notification of AEs
- Public access to safety data and reports
• Utilisation of electronic healthcare records for ‘real-time’
pharmacovigilance?
• Development of methods for risk minimisation, and
assessment of their effectiveness?
• Increased litigation & media attention to drug safety?

Pharmacovigilance in real life may 12

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