An agency of the European Union Presented by: Tomasz Jabłoński Legal Administrator, Legal Service...

An agency of the European Union

Presented by: Tomasz JabłońskiLegal Administrator, Legal Service - Directorate

Implementation of the New Pharmacovigilance Legislation HMPWG meetingWarsaw, 7-8 December 2011

Implementation of the New Pharmacovigilance Legislation2

• New pharmacovigilance legislation: Why?• New pharmacovigilance legislation: How?• New pharmacovigilance legislation: What?• New pharmacovigilance legislation: What to

deliver?• Conclusions

In this presentation


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


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.


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.


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

Why: high level objectives (1/2)


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

Why: high level objectives (2/2)


• 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

• 2006-2008: 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

How: making of new legislation by the European Commission (1/3)


• 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



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)



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


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


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


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


PRAC and Decision-making:

• 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

What: PRAC and decision-making (1/5)



• PRAC and Decision-making:

– 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



• PRAC and Decision-making:

- 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


What: PRAC and decision-making (4/5)Single AR prepared by the Member State

appointed by the CMD

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

Decision sent the MAHs and MSs concerned

Position of the majority of MSs to be sent to the Commission which will

adopt a decision

Detailed explanations to be annexed. CMD has the legal power

MS ≠

CMD ≠ PRACMS =

“No CAP concerned”



Single AR prepared by the Rapporteur appointed by the PRAC

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)

“At least 1 CAP concerned”


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


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


Risk Management planning:

• 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

What: Risk Management planning (1/2)


• 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)

What: Risk Management planning (2/2)


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



• 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



• 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


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

What: PASS/PAES (1/2)


• 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

What: PASS/PAES (2/2)


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


• 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

What: signal detection (1/2)


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


• ‘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 (…)

What: EU medicinal product dictionary


• 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

What: transparency and communication


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.


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


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)


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


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


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 ‘For the fulfilment of its pharmacovigilance tasks including fulfilment of its pharmacovigilance tasks including agreement and monitoring of risk management systems, agreement and monitoring of risk management systems, it (CHMP) shall rely on scientific assessment and it (CHMP) shall rely on scientific assessment and recommendations of the PRAC’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



• 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)



• 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


• 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

What to deliver:

governance structure for EMA tasks (1/6)

Implementation of the New Pharmacovigilance Legislation43 Implementation of the New Pharmacovigilance Legislation43

Project Oversight Committee(ERMS-FG)

Project Coordination

Group

EMA/MSsProject Team 1 - Audit/

Inspections

EMA/MSsProject Team 2PSURs

EMA/MSsProject Team 3

ADR reporting/Additional Monitoring/

-Signals

EMA/MSsProject Team 4-RMP/

PASS/PAES-Effectiveness

of risk Minimisation


-Committees/Referrals


-Communica-tion/

Transparency

12 EMA Subproject TeamsPSUR

PASS/PAES

Product Info.

EV/ADR rep.

Committees

Referrals

Fees

Com./Transp

Lit. monit/Signal detect.

Insp./PhV sy.

RMS

PhV audits

What to deliver:

governance structure for EMA tasks (2/2)

6 EMA/MSs Project Teams

EMA Task-Force


What to deliver: working methodology

Subproject Teams

Project Teams

IssueLog

ActionsTable

TrackingTable

ConceptPaper

Impl.Meas.

StatusReport

ConceptPaper

Impl.Meas.

Project Coordination

Group

TrackingTable

ActionsTable

Project OversightERMS FG

ConceptPaper

ConceptPaper

Impl.Meas.

Impl.Meas.

Drafted

Drafted/Agreed

Adopted

Adopted

IssueLog

StatusReport

StatusReport


What to deliver: reporting timelinesFriday

2 weeks before CHMP

FridayWeek before CHMP

WednesdayCHMP week

Wednesday Week after CHMP

Subproject Teamssubmit Status Report

Project Teamssubmit Status Report

Project Coord. Groupsubmits Status Report

to ERMS FG

Project Coord. Groupmeets to review Status

Reports


Q1 – Q2 2011Phase I

Q3 2011 – Q3 2012Phase II

-First round ofBusiness Process Mapping-IT requirements

-Technical contribution to EC draft implementing measures- Format of productInformation (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

-Documentation update

-ICT tools maintenance

What to deliver: implementation phasing plan

Implementation of the New Pharmacovigilance Legislation47 Implementation of the New Pharmacovigilance Legislation47

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


What to deliver:

Hierarchy of rules Deliverables

- Regulation (EU) 1235/2010 - Directive 2010/84/EU

EC Implementing Measures

= Commission Regulation(Reg. Art. 87a and Dir.Art.108

- Policies - Operations

- ICT

Concept Papers

IT requirements

Process Mapping

EMA/MSsTechnical contribution

Guidelines

SOP/WIN/Templates

IT tools


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


3 10 17 24 31 7 14 21 28 7 14 21 28 4 11 18 25 2 9 16 23 30 6 13 20 27 4 11 18 25 1 8 15 22 29 5 12 19 26 3 10 17 24 31 7 14 21 28 5 12 19 26

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Topics Activity1. Periodic Safety Update Reports 1.1 Implementing measures (Reg. Art. 87a(f)) Draft content Peer-review Finalisation Adopt (ERMS) EC Consultation and Adoption

1.2 Business processes Design business processes1.3 SOP/WIN/Template/Guideline Preparation of SOP/WIN/Template/Guidelines1.4 IT requirements Define IT requirements1.5 Plan audit on PSUR repository*

2. PASS/PAES 2.1 Implementing measures (Reg. Art. 87a(g)) Draft content Peer-review Finalisation Adopt (ERMS) EC Consultation and Adoption 2.2 Business processes Design business processes2.3 SOP/WIN/Template/Guideline Preparation of SOP/WIN/Template/Guidelines2.4 IT requirements Define IT requirements

3. Product Information 3.1 Implementing measures (Reg. Art. 87a(c)) Draft content Peer-review Finalisation Adopt (ERMS) EC Consultation and Adoption 3.2 Business processes Design business processes3.3 SOP/WIN/Template/Guideline Preparation of SOP/WIN/Template/Guidelines3.4 IT requirements Define IT requirements

4. EudraVigilance/Adverse Drug Reactions reporting 4.1 Implementing measures (Reg. Art. 87a(e)) Draft content Peer-review Finalisation Adopt (ERMS) EC Consultation and Adoption 4.2 Business processes Design business processes4.3 SOP/WIN/Template/Guideline Preparation of SOP/WIN/Template/Guidelines4.4 IT requirements Define IT requirements4.5 Plan audit on EV*

5. Committees 5.1 Business processes Design business processes5.2 Rules of procedure/Mandate Preparation of rules of procedure/mandate Consultation Adoption5.3 Committee membership Nomination process5.3 SOP/WIN/Template/Guideline Preparation of SOP/WIN/Template/Guidelines5.4 IT requirements Define IT requirements

6. Referrals 6.1 Business processes Design business processes6.2 SOP/WIN/Template/Guideline Preparation of SOP/WIN/Template/Guidelines6.3 IT requirements Define IT requirements

7. Fees*8. Communication/Transparency 8.1 Business processes Design business processes

8.2 Define common strategy Draft Concept Paper Consultation Finalisation Adopt (ERMS)8.3 SOP/WIN/Template/Guideline Preparation of SOP/WIN/Template/Guidelines8.4 IT requirements Define IT requirements

9. Literature Monitoring/Signal Detection 9.1 Implementing measures (Reg. Art. 87a(d)) Draft content Peer-review Finalisation Adopt (ERMS) EC Consultation and Adoption 9.2 Business processes Design business processes9.3 SOP/WIN/Template/Guideline Preparation of SOP/WIN/Template/Guidelines9.4 Plan for outsourcing of literature monitoring*

10. Inspections/Pharmacovigilance Systems 10.1 Implementing measures (Reg. Art. 87a(a-b)) Draft content Peer-review Finalisation Adopt (ERMS) EC Consultation and Adoption 10.2 Business processes Design business processes10.3 SOP/WIN/Template/Guideline Preparation of SOP/WIN/Template/Guidelines10.4 IT requirements Define IT requirements

11. Risk Management Systems 11.1 Implementing measures (Reg. Art. 87a(f)) Draft content Peer-review Finalisation Adopt (ERMS) EC Consultation and Adoption 11.2 Business processes Design business processes11.3 SOP/WIN/Template/Guideline Preparation of SOP/WIN/Template/Guidelines11.4 IT requirements Define IT requirements

12. Pharmacovigilance Audits 12.1 Business processes Design business processes12.2 Define common strategy Draft Concept Paper Consultation Finalisation Adopt (ERMS)12.3 SOP/WIN/Template/Guideline Preparation of SOP/WIN/Template/Guidelines12.4 IT requirements Define IT requirements

13. Information Technology tools 13.1 Consolidate IT requirements Consolidation13.2 Plan for IT development*

2011Sep Oct NovJan Feb Mar Apr May Jun Jul Aug Dec

4. Stakeholders' meetings5. Management Board meetings

6. HMA meetings

Meetings1. EMA Task-Force meetings2. Project Teams' meetings

3. ERMS FG meetings

Overall implementation plan: key

activities


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


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

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