1. Implementation of the New Pharmacovigilance Legislation
HMPWG meeting
Warsaw, 7-8 December 2011
Presented by: Tomasz Jabłoński
Legal Administrator, Legal Service - Directorate

2. In this presentation New pharmacovigilance legislation: Why?
New pharmacovigilance legislation: How?
New pharmacovigilance legislation: What?
New pharmacovigilance legislation: What to deliver?
Conclusions
Implementation of the New Pharmacovigilance Legislation

3. Why: to further strengthen pharmacovigilance (1/2)
EC impact assessment:
5% of all hospital admissions are for ADRs, 5% of all hospital patients suffer an ADR, 5th most common cause of hospital death
Estimated 197,000 deaths per year in EU from ADRs
Societal cost of Euro 79 Billion
Cost savings to society from the legislation in range Euro 237 Million – 2.4 Billion
Health savings between 591 and 5910 lives saved per year
Implementation of the New Pharmacovigilance Legislation

4. Why: to further strengthen pharmacovigilance (2/2)
Annual industry spending on PhV Euro 833 Million
Annual industry savings from the proposals Euro 145 Million (17.4%)
Cost to EMA:
Euro 3.9 million set up cost
Euro 10.1 million annual running costs (covered by new fees)
Significant changes to the EMA tasks during the co-decision procedure.
Implementation of the New Pharmacovigilance Legislation

5. Why: high level objectives
The new regulation and directive on pharmacovigilance constitute the biggest change in legal framework for the EMA since its establishment in 1995.
The provisions impact far beyond a narrow definition of pharmacovigilance and risk management.
Implementation of the New Pharmacovigilance Legislation

6. Why: high level objectives (1/2)
Promote and protect public health by reducing burden of ADRs and optimising the use of medicines:
Clear roles and responsibilities
Risk based/proportionate
Increased proactivity/planning
Reduced duplication/redundancy
Integrate benefit and risk
Implementation of the New Pharmacovigilance Legislation

7. Why: high level objectives (2/2)
Promote and protect public health by reducing burden of ADRs and optimising the use of medicines (cont’d):
Ensure robust and rapid EU decision-making
Strengthen the EU Network
Engage patients and healthcare professionals
Increase transparency and accountability
Provide better information on medicines
Implementation of the New Pharmacovigilance Legislation

8. How: making of new legislation by the European Commission (1/3)
2003: EC decision to undertake an assessment of the Community system of pharmacovigilance
2005: Independent study completed to map the strengths and weaknesses of the EU system
: Research, consultation, policy development
December 2008: “Pharma package” (PhV, information to patients and falsified medicines) adopted by the European Commission and transmitted to Council and European Parliament for co decision procedure to start
Implementation of the New Pharmacovigilance Legislation

9. How: making of new legislation by the European Commission (2/3)
Co-decision work starts on revisions to Directive 2001/83/EC and revisions to Regulation (EC)2004/726
23 June 2010: Agreement on final text (first reading agreement)
22 September 2010: Final favourable vote in the European Parliament
Implementation of the New Pharmacovigilance Legislation

10. How: making of new legislation by the European Commission (3/3)
Publication in OJ L 348
Regulation (EU) No 1235/2010 of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, and Regulation (EC) No 1394/2007 on advanced therapy medicinal products (applicable from 2 July 2012)
Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use (applicable from 21 July 2012)
Implementation of the New Pharmacovigilance Legislation

11. How: further amendments envisaged
‘(…) in view of recent pharmacovigilance events in the EU, the Commission has detected certain areas where the legislation could be further strengthened’
Amended EC proposal for a Regulation amending Regulation (EC) 726/2004 as regards information to the general public on medicinal products subject to medical prescription and as regards pharmacovigilance
Amended EC proposal for a Directive amending Directive 2001/83/EC, as regards information to the general public on medicinal products subject to medical prescription and as regards pharmacovigilance
Implementation of the New Pharmacovigilance Legislation

12. Impact on homeopathic medicinal products
Article 16(3) Dir. 2001/83/EC:
‘Title IX [Pharmacovigilance] shall apply to homeopatic medicinal products, with the exception of those referred to in Article 14(1)’
References to HMP registered according to the simplified procedure (Article 14 Dir. 2001/83/EC) in the amended Regulation (EC) 726/2004
Implementation of the New Pharmacovigilance Legislation

13. What: key changes for ADRs (1/2)
Better ADR Reporting
New ADR definition:
‘A response to a medicinal product which is noxious and unintended’
So far:
‘A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoriation, correction or modification of physiological function 13
Implementation of the New Pharmacovigilance Legislation

14. What: key changes for ADRs (2/2)
Medication errors that result in an ADR are reported
Patient reporting – the debate on ‘if’ is over! Now debate ‘how’!
After transitional period:
All ADRs from companies and from Member States are sent to Eudravigilance only (MSs only get their national reports and industry accesses reports via EudraVigilance) with major increases in data volumes - from 40,000 now to 100,000 case reports per month anticipated,
Member States are ‘auto-forwarded’ their national data
Companies access reports in Eudravigilance
Implementation of the New Pharmacovigilance Legislation

15. What: PRAC and decision-making (1/5)
New Pharmacovigilance Risk Assessment Committee
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
Implementation of the New Pharmacovigilance Legislation

16. What: PRAC and decision-making (2/5)
Composition:
Members/alternates appointed by each MS
6 members appointed by Commission
1 member/alternate representing health care professionals
1 member/alternate representing patients associations
with a view to ensuring that the relevant expertise is available within the Committee, including clinical pharmacology and pharmacoepidemiology, on the basis of a public call for expressions of interest
Possible delegation from only one MS to another (max 1)
Collaboration with CHMP rapporteur or the reference MS
Implementation of the New Pharmacovigilance Legislation

17. What: PRAC and decision-making (3/5)
- Role:
Interaction with CHMP/coordination group recommendations forwarded to
CHMP for opinion
Coordination group for agreement
Justification if not in accordance with recommendations
PRAC recommendations publicly available with opinion/agreement
Agreement and monitoring RMPs
Implementation of the New Pharmacovigilance Legislation

18. What: PRAC and decision-making (4/5)
Single AR prepared by the Member State appointed by the CMD
“No CAP concerned”
PRAC to adopt the AR
If any regulatory action results from the AR, CMD to reach a position: maintenance, variation, suspension or revocation + according timetable for implementation
MS =
CMD ≠ PRAC
MS ≠
Decision sent the MAHs and MSs concerned
Detailed explanations to be annexed. CMD has the legal power
Position of the majority of MSs to be sent to the Commission which will adopt a decision
Implementation of the New Pharmacovigilance Legislation

19. What: PRAC and decision-making (5/5)
Single AR prepared by the Rapporteur appointed by the PRAC
“At least 1 CAP concerned”
PRAC to adopt the AR
If any regulatory action results from the AR, CHMP to adopt an opinion: maintenance, variation, suspension or revocation + according timetable for implementation
Commission to adopt a decision concerning the regulatory action(s)
Implementation of the New Pharmacovigilance Legislation

20. What: referrals (1/2)
New ‘urgent Union procedure’ replaces current Article 107 and can include CAPs
Article 36 deleted
2 procedures for pharmacovigilance data, depending on urgency:
Article 107i urgent procedure
Article 31 all other cases
All pharmacovigilance referrals go to PRAC – PRAC to issue recommendation
Implementation of the New Pharmacovigilance Legislation

21. What: referrals (2/2) EMA can enlarge scope of referrals
‘May’ clause re. public hearing (with EMA guidance on when and how),
Member States retain discretion of when to refer (the original Commission concept of automatic referrals is lost)
To be applied to all products (including centralised)
New role for the Coordination Group on the decision making process
Article 20 for pharmacovigilance data also goes to PRAC
Implementation of the New Pharmacovigilance Legislation

22. What: Risk Management planning (1/2)
New definition of a ‘risk management system’ : ‘a set of pharmacovigilance activities and interventions, such as studies and reports, designed to identify, characterise, prevent or minimise risks relating to a medicinal product, including the assessment of the effectiveness of those activities and interventions’
New definition of a ‘Risk management plan’: ‘ a detailed description of the risk management system’
Requirement for all new products but risk proportionate
Implementation of the New Pharmacovigilance Legislation

23. What: Risk Management planning (2/2)
Legal basis to require a risk management system/ plan for an authorised product. (‘if there are concerns about the risks affecting the risk-benefit balance’)
Safety and efficacy studies included (move towards integrated B/R)
Systematic role for the new Committee (PRAC)
Implementation of the New Pharmacovigilance Legislation

24. What: Periodic safety update reports (PSURs) (1/3)
Content:
Summaries of data relevant to the BR of the medicinal product, incl. results of all studies with a consideration of their potential impact on the marketing authorisation
A scientific evaluation of the R-B balance of the medicinal product
All data relating to the volume of sales of the medicinal product and any data in possession of the MAH relating to the volume of prescriptions, incl. an estimate of the population exposed to the medicinal product
Implementation of the New Pharmacovigilance Legislation

25. What: Periodic safety update reports (PSURs) (2/3)
Submitted electronically to EMA (where Member States access)
Some products categories (e.g. generics, homeopathic medicinal products registered according to the simplified procedure, traditional herbal medicinal products) exempted from ‘regular’ submissions. PSURs required only:
- where such obligation has been laid down as a condition in the MA
- when requested by a competent authority on the basis of concerns relating to PhV data or due to the lack of PSURs relating to an active substance after MA has been granted
Implementation of the New Pharmacovigilance Legislation

26. What: Periodic safety update reports (PSURs) (3/3)
For established substances, single EU assessment for all products
Assessment leads to automatic regulatory action: variations, suspension, revocation
Periodicity will be established by EMA (binding list on website)
Likely to replace many referrals
Implementation of the New Pharmacovigilance Legislation

27. What: PASS/PAES (1/2)
Strengthened legal basis to require post-authorisation studies:
post-authorisation safety study (PASS)
post-authorisation efficacy study (PAES)
Regulators can require study by industry at first authorisation
Regulators can require study by industry post-authorisation
Implementation of the New Pharmacovigilance Legislation

28. What: PASS/PAES (2/2)
Study is a condition of the authorisation and is legally binding
In the event that the same safety concern applies to more than one medicinal product, the EMA / national competent authority shall …… encourage the marketing authorisation holders concerned to conduct a joint post-authorisation safety study
Implementation of the New Pharmacovigilance Legislation

29. What: medicinal products subject to additional monitoring
New active substances
New MA biological products (including biosimilars)
Any other upon request (+PRAC) for products specific requirements in the RMP
Symbol and statement and standardised explanatory sentence in SmPC and leaflet
Deletion from the list after 5 years or conditions met
Implementation of the New Pharmacovigilance Legislation

30. What: signal detection (1/2)
For first time the concept is recognised
Clear roles and responsibilities for EMA and Member States; EMA will lead the signal detection for CAPs and support and coordinate signal detection by the MSs for NAPs
Minimum standards for signal detection will be the subject of a legally binding Commission regulation and of independent audit
‘Monitor the data in the EudraVigilance database to determine whether there are new risks or whether risks have changed and whether those risks impact on the risk benefit balance’
PRAC performs initial analysis and prioritisation of signals of new risks or risks that are changing or changes to the R-B balance
Implementation of the New Pharmacovigilance Legislation

31. What: signal detection (2/2)
Increased ADR volumes need to be analysed
Signal detection linked to patient reporting will be required
Signal detection linked to PSURs will be required
For NAPs there is a need to develop new procedures and analyses
Implementation of the New Pharmacovigilance Legislation

32. What: EU medicinal product dictionary
‘The Agency shall establish a list of all medicinal products authorised in the Community. To this effect the following measures shall be taken:
(a) the Agency shall…..make public a format for the electronic submission of medicinal product information
(b) MAHs shall, by (18 months after the entry into force of regulation), electronically submit to the Agency information for all medicinal products authorised or registered in the Community, using the format referred to in point (a);
(c) from the date set out in point (b), MAHs shall inform the Agency of any new or varied authorisations (…)
Implementation of the New Pharmacovigilance Legislation

33. What: transparency and communication
EU and national medicines web-portals linked together
MSs to add their product information to their national web-portals
Dramatic increase in transparency (all assessment conclusions public)
EMA to coordinate MSs safety announcements on NAPs (as well as CAPs)
Public hearings
Overall the communication/networking/transparency provisions will require significant IT (for web-portal) and staff resources
Implementation of the New Pharmacovigilance Legislation

34. What: key changes keeping product info up to date
MAH shall inform of any prohibitions or restrictions or any new information which may influence the evaluation of benefits and risks….’include both positive and negative results of clinical trials or other studies in all indications and populations, whether or not included in the marketing authorisation, as well as data on use of the medicinal product where such use is outside the terms of the marketing authorisation’.
MAH shall keep their product information up to date with current scientific knowledge, including the conclusions of the assessments and recommendations on the EU medicines web-portals
Regulators may at any time ask the MAH to forward data demonstrating that the BR balance remains favourable. MAH shall answer fully and promptly any such request. 34
Implementation of the New Pharmacovigilance Legislation

35. Funding pharmacovigilance activities
EMA to collect fees for pharmacovigilance activities for services provided by the EMA or Coordination Group
Rapporteurs to be paid by the EMA
Fees for pharmacovigilance, literature monitoring, information technology tools, provision of information to the public
Payment rapporteurs providing assessment for Union pharmacovigilance procedures, PSURs, PASSs protocols and risk management systems
Implementation of the New Pharmacovigilance Legislation

36. Further changes – EC proposals
Article 23 Reg. (list of medicinal products subject to additional monitoring
Article 20 Reg. (clarification of respective scopes of this provision)
Article 107i Dir. (automatic procedure at EU level in the cases of specific serious safety issues with NAPs)
Article 13 and Article 14b Reg. / Article 23a and 123 Dir. (in order to avoid that voluntary withdrawal of a MA could lead to safety issues not being addressed in the EU)
Implementation of the New Pharmacovigilance Legislation

37. Implementing measures (1/2) Reg. (EC) 726/2004 Art. 87a Dir
Implementing measures (1/2) Reg. (EC) 726/2004 Art. 87a Dir. 2001/83/EC Art. 108
After public consultations (deadline: 7 November 2011)
The content and maintenance of the pharmacovigilance system master file kept by the MAH
The minimum requirements for the quality system for the performance of pharmacovigilance activities by the Agency (the NCAs and MAH)
The use of internationally agreed terminology, formats and standards for the performance of pharmacovigilance activities
Implementation of the New Pharmacovigilance Legislation

38. Implementing measures (2/2) Reg. (EC) 726/2004 Art. 87a Dir
Implementing measures (2/2) Reg. (EC) 726/2004 Art. 87a Dir. 2001/83/EC Art. 108
The minimum requirements for the monitoring of data included in the EV database to determine whether there are new risks or whether risks have changed
The format and content of electronic transmission of suspected adverse reactions by MSs and MAHs
The format and content of electronic PSURs and RMPs
The format of protocols, abstracts and final study reports of the PASS
Implementation of the New Pharmacovigilance Legislation

39. Clarification of roles (1/3)
EMA
Scientific and coordinating role reinforced
New scientific committee Pharmacovigilance Risk Assessment Advisory Committee (PRAC) with important role ‘For the fulfilment of its pharmacovigilance tasks including agreement and monitoring of risk management systems, it (CHMP) shall rely on scientific assessment and recommendations of the PRAC’
Key role for EMA and PRAC in signal detection and follow up
Remuneration by EMA contract with rapporteurs for PSURs, Union procedures
Implementation of the New Pharmacovigilance Legislation

40. Clarification of roles (2/3)
Member States
Conducting pharmacovigilance for products on their market, signal detection and follow up
Operation of the pharmacovigilance system
Increased cooperation and worksharing
Improvement coordination group (alternates, EMA support, remuneration, decision making process)
Penalties for non-compliance
+ other obligations (Article 102 Dir. 2010/84/EU)
Implementation of the New Pharmacovigilance Legislation

41. Clarification of roles (3/3)
MAHs
Operation pharmacovigilance system
Summary to authorities
Detailed updated pharmacovigilance system master file on site (inspection)
Risk management system (proportionate to risks) in all MA
Continuous monitoring of safety information and update MA
Implementation of the New Pharmacovigilance Legislation

42. What to deliver: governance structure for EMA tasks (1/6)
Need to cope with the
Complexity of the network
Number of (scientific) fora directly affected by the new legislation and providing input into the preparation for the implementation
Need for
Consensus – building within the network
Interaction with stakeholders
Implementation of the New Pharmacovigilance Legislation

43. What to deliver: governance structure for EMA tasks (2/2)
Project
Oversight
Committee
(ERMS-FG)
Project
Coordination
Group
6 EMA/MSs Project Teams
EMA/MSs
Project
Team 1
- Audit/
Inspections
EMA/MSs
Project
Team 2
PSURs
EMA/MSs
Project
Team 3
ADR reporting
/Additional
Monitoring/
-Signals
EMA/MSs
Project
Team 4
-RMP/
PASS/PAES
-Effectiveness
of risk
Minimisation
EMA/MSs
Project
Team 5
-Committees/
Referrals
EMA/MSs
Project
Team 6
-Communica-
tion/
Transparency
12 EMA Subproject Teams
EMA Task-
Force
PSUR
Product Info.
Committees
Fees
Lit. monit/
Signal detect.
RMS 43
Implementation of the New Pharmacovigilance Legislation
Implementation of the New Pharmacovigilance Legislation
PASS/PAES
EV/ADR rep.
Referrals
Com./Transp
Insp./PhV sy.
PhV audits

44. What to deliver: working methodology
Project
Oversight
ERMS FG
Status
Report
Concept
Paper
Impl.
Meas.
Adopted
Project
Coordination
Group
Status
Report
Concept
Paper
Impl.
Meas.
Adopted
Drafted/
Agreed
Project
Teams
Actions
Table
Issue
Log
Tracking
Table
Status
Report
Concept
Paper
Impl.
Meas.
Subproject
Teams
Actions
Table
Issue
Log
Tracking
Table
Concept
Paper
Impl.
Meas.
Drafted 44
Implementation of the New Pharmacovigilance Legislation

45. What to deliver: reporting timelines
Friday
2 weeks before CHMP
Subproject Teams
submit Status Report
Friday
Week before CHMP
Project Coord. Group
submits Status Report
to ERMS FG
Project Teams
submit Status Report
Wednesday
Week after CHMP
Project Coord. Group
meets to review Status
Reports
Wednesday
CHMP week 45
Implementation of the New Pharmacovigilance Legislation

46. What to deliver: implementation phasing plan
Q1 – Q2 2011
Phase I
Q – Q3 2012
Phase II
First round of
Business Process Mapping
-IT requirements
Technical contribution to EC draft implementing measures
Format of product
Information (Reg. Art.57)
-Key papers
Good Vigilance Practice and other guidelines
Second and third rounds of Business Process Modelling
Standard Operating Procedures, Working Instructions, Templates
RoP, Mandate
ICT tools development
July 2012
-Documentation update
-ICT tools maintenance
Implementation of the New Pharmacovigilance Legislation

47. What to deliver: prioritisation
EMA/MSs technical contribution to EC Implementing measures (priority)
Business process mapping
IT requirements supported by business process mapping
Concept papers (for policy issues)
Good Vigilance Practice guidelines
SOPs/WINs/Templates 47
Implementation of the New Pharmacovigilance Legislation
Implementation of the New Pharmacovigilance Legislation

48. What to deliver: Hierarchy of rules Deliverables
EMA/MSs
Technical contribution
Guidelines
SOP/WIN/Templates
IT tools
Concept Papers
Process Mapping
IT requirements
Implementation of the New Pharmacovigilance Legislation

49. What to deliver: interaction with stakeholders
Stakeholders meetings involving EMA, Member States, EC, industry, patients and healthcare professionals representatives
Positive feedback from 3 stakeholders meeting held at EMA’s permisses
Scheduling of additional Stakeholders forum will be based on content development
Implementation of the New Pharmacovigilance Legislation

50. Overall implementation plan: key activities50
Implementation of the New Pharmacovigilance Legislation

51. Conclusions: EMA is the hub of the European network
New legislation:
opportunity to strengthen and rationalise public health
Major work to ensure full and effective implementation
Resources are needed
Collaboration will be key 51
Implementation of the New Pharmacovigilance Legislation

52. THANK YOU. Any questions
THANK YOU! Any questions? The views expressed in this presentation are those of the author and do not necessarily reflect and cannot be quoted as the views of the European Medicines Agency
Implementation of the New Pharmacovigilance Legislation