The document summarizes key points about pharmacovigilance from an industry perspective. It discusses the historical milestones that demonstrated the importance of pharmacovigilance. It then describes pharmacovigilance processes, including adverse event reporting, signal detection, and risk management plans. Finally, it outlines the new EU legislation's aim to strengthen and rationalize the EU pharmacovigilance system through requirements for pharmacovigilance systems and increased transparency.
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Pharmacovigilance in real life may 12
1. Pharmacovigilance in
Real Life
An Industry Perspective
Barry Arnold
EU Qualified Person for Pharmacovigilance
AstraZeneca
2. 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
4. Historical Milestones
……. 50 years ago
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
5. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
6. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
7. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
8. “Show me a drug without side-
effects and I shall show you a drug
that does not work”
Dunlop
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
9. PV in real life | May 2012 Global Medicines Development | Chief Medical Office
10. PV in real life | May 2012 Global Medicines Development | Chief Medical Office
11. PV in real life | May 2012 Global Medicines Development | Chief Medical Office
12. PV in real life | May 2012 Global Medicines Development | Chief Medical Office
14. 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).
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
15. Pharmacovigilance has no boundaries
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
16. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
17. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
18. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
19. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
20. AstraZeneca Case Handling Process
Queries Queries
Reporter/ Data Entry Site
AZ staff
Investigator JASPER
MC/CRO
Marketing Companies
Regulatory Authorities
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
21. 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)
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
22. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
23. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
24. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
25. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
26. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
28. 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.
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
29. 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)
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
30. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
31. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
32. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
33. 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’
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
34. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
35. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
36. 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
PV in real life | May 2012 Global Medicines Development | Chief Medical Office
37. 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?
PV in real life | May 2012 Global Medicines Development | Chief Medical Office