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EU Pharmacovigilance
Legislation (EU NL)
• Regulatory Implementation status
• Overview and industry challenges
April-2014
QPPV Office
Global Pharmacovigilance & Epidemiology
Sanofi
Anne-Marie De-Ferran
Associate VP QPPV Office
Manager QPPV Office&PV
Policy
Global Pharmacovigilance&
Epidemiology
LPC Newcomers – October 14th to 15th – Chilly-Mazarin
EU Legal Framework for Pharmacovigilance
Applicable to the 28 Member States and
Adopted by Norway, Iceland & Liechtenstein
[European Economic Area (EEA) countries]
2
3
Regulatory Network
Key European Authorities in PV
Heatlh Authorities of each Member State
National Competent Authorities (NCA)
The Co-ordination Group for Mutual Recognition and Decentralised
Procedures – Human, examine any question relating to marketing
authorisation of a medicinal product in two or more Member States in
accordance with the mutual recognition procedure or the decentralised
procedure
Helps protect and promote health in Europe by evaluating medicines
for both human and veterinary use
EMA
Executive body of the European Union
responsible for proposing legislation,
implementing decisions, upholding the
Union's treaties and day-to-day
running of the EU
The Committee for Medicinal Products for Human Use is the committee
at the EMA that is responsible for preparing opinions on questions
concerning medicines for human use.
CHMP
The committee at the EMA that is responsible for assessing and
monitoring safety issues for human medicines.
PRAC
Agenda
● Regulatory Implementation status
● Overview of Major Regulatory Milestone of the EU Pharmacovigilance
Legislation
● Industry Challenges
4
EU PL – REGULATORY
IMPLEMENTATION STATUS
|
5
6
EU Pharmacovigilance Legislation
Regulation
1235/2010
1027/2012
Directive
2010/84/EU
2012/26/EU
Applies on 2-Jul-2012
Applies on 5-Jun-2013
some articles apply on 4 Dec 2012
Applies on 21-Jul-2012
Applies on 28-Oct-2013
Promote and protect public health
by reducing burden of ADRs and
optimising the use of medicines
 Clear roles and responsibilities
 Robust and rapid EU decision-making
 Engage patients and healthcare
professionals
Implementing Regulation
520/2012
198/2013 ()
Applies on 10-Jul-2012
 Science based - integrate benefit and risk
Art.29/ 38 apply on 10 Jan 2013
 Risk based/proportionate
Applies on 31-Dec-2013.
PV fees – Regulation (draft)
PAES delegated act (draft)
 Increased pro activity/planning
 Reduced duplication/redundancy
 Increase transparency and provide better
Good Pharmacovigilance Practices (GVP)
information on medicines
Regulatory & procedural guidance
EMA Information & Communication
Learn more on EU-PL:
EMA website
European Commission website
Directive 2010/84/EU Transposition
in Member States
●
Overview of the transposition status from the Directive 2010/84/EU within each Member State
 Directive effective date at National Level: 21-July-2012 (MRP/DCP products)
 National Legislation release date:
EU
Member
State
National
legislation
released date
(P=planned)
EU
Member State
AUSTRIA
14-Dec-2012
LATVIA
BELGIUM
10-Jun-2013
LIECHTENSTEIN
BULGARIA
21-Dec-2012
LITHUANIA
CYPRUS
31-May-2012
LUXEMBOURG
CROATIA
July 2013
National
legislation
released date
(P=planned)
01-Feb-2013
-
-
MALTA
30-Oct-2012
08-Feb-2013
06-Mar-2013
THE
NETHERLANDS
DENMARK
12-Jul-2012
01-Aug- 2012
NORWAY
-
ESTONIA
23-Jul-2012
POLAND
25-Oct-2013
FINLAND
22-May-2013
PORTUGAL
14-Feb-2013
FRANCE
29-Dec-2011/
09-Nov-2012
ROMANIA
21-Jul-2012
GERMANY
26-Oct-2012
SLOVAKIA
01-Sept-2012
Sep-2012
SLOVENIA
07-Mar-2014
SPAIN
26-Jul-2013
SWEDEN
21-Jun-2012
UNITED KINGDOM
14-Aug-2012
HUNGARY
17-Jul-2012
ICELAND
-
IRELAND
27-Aug-2012
ITALY
-
National
Legislation:
Nov-2012
CZECH
REPUBLIC
GREECE
EU NPL Transposition Status
in 31 Member States
26
Final
5 No
Draft
Last update: 01-April-2014
EU PV legislation status
● Implementation of the Pharmacovigilance legislation in July 2012


March 2014 : In EEA, final transposition of Directive 2012/84/EU into 26
national legislations (5 missing)
Amendment on directive and regulation released in Q3 2012 following
“Mediator stress test”
● The majority of the 15 GVP Modules has been now published,
pieces are still expected.
● “Pharmacovigilance” legislation in name only


Global impact; leaves virtually no function untouched
Massive changes in multiple processes required, new skill sets required.
● Lack of harmonisation with non-EEA countries

Increased bureaucratic burden with no contribution towards promoting
patient safety.
8
Updates to the PV legislation since July 2012
● Amendment of the PV legislation
 Recent pharmacovigilance incidents in the EU have shown the need to strengthen
three aspects of the pharmacovigilance legislation
 Release of Dir. 2012/26/EU [25 Oct. 2012] / Reg. (EU) 1027/2012 [14 Nov. 2012]
Main focus on:
• In case of urgent safety issue Automatically assessed at European level [Art 107i (Dir.)]
• Notification of MA status WW when safety concern [Art 23a (Dir) / Art 13a (Reg) – Art 14b (Reg.) / Art 123 (2) (Dir.) ]
• Art 23 (Reg) (c)-(d)
● GVP modules status
 5 New, 3 Revised, 3 Expected
● Implementing Regulation 198/2013 on black symbol of 7 March 2013
 Adopt black symbol (▼) to identify medicinal products that are subject to additional
monitoring
● PAES
 Delegated act on PAES - Public consultation conducted from Nov. 2012 till Feb. 2013
● Future PV fees
9
EU NPL – OVERVIEW AND
INDUSTRY CHALLENGES
Major Regulatory Milestones
PSMF
Fees
Transparency
xEVMPD
WW MA status notification
PRAC
Additional Monitoring
Referral
RMP
ICSR Management
and Reporting
PASS/ PAES
Renewals
Signal Detection
and Screening
New PSUR/ PBRER
Transparency and Communication
● Creation of medicines web-portals (EMA and each Member State)







PRAC Agenda, Minutes, including signal detection activities
List of products subject to additional safety monitoring
Summary of RMP for lay public
PASS protocols and public abstract of results
Community Reference Dates and frequency of PSUR submission
Final assessment conclusions of PSUR and Urgent Union Procedure
Information on Urgent Union Procedures
● EU coordinated communication about safety issues

For products authorised in more than one Member States, EMA responsible for coordination
(timetables) of safety announcements between national Competent Authorities
● Eudravigilance publicly accessible


Online publication of suspected side effect reports since May 2012 (Centrally Authorised Products)
Information on Medicinal Products (xEVMPD)
Industry challenges
• Keep control over public information when product data is made available on web portals in the EEA,
anticipate the consequences in the rest of the world
PRAC (PV Risk Assessment Committee)
●
EMA 7th scientific Committee (Replacing the PhVWP)
 Members: EU National Agencies, HCP and Patients representatives
 Key role in PV assessments: mandatory or consultative role
• Referrals (Art 20, 31, 107i)
• Additional monitoring
• PSUR
• RMP
• PASS protocols and results
• Renewals & annual assessment
• Signal detection
• Type II safety variations
• Safety communication
• PV audits, inspections requests & results
• EURD lists
●
Safety concerns : A major change in EU decision making process for safety issues
 Rapid risks evaluation in the context of the identified benefits
●
Final responsibility for opinion on the risk-benefit remains with CHMP (centralised products)
or CMDh (other products)
Industry challenges
• Follow-up PRAC activities, answer all questions, coordinate with other MAHs.
• Direct Healthcare Professional Communication (DHPC) & communication plan related to medicinal
products authorised in more than one Member State should be referred to the PRAC / EMA coordination.
PRAC - Responsibilities
● “The Pharmacovigilance Risk
Assessment Committee (PRAC) is
responsible for assessing all aspects of
the risk management of the use of
medicinal products [human use]
approved in EEA.
● This includes the detection, assessment,
minimisation and communication relating
to the risk of adverse reactions, having
due regard to the therapeutic effect of the
medicinal product.
● It is responsible for the design and
evaluation of post-authorisation safety
studies and pharmacovigilance audit.”
Source: EMA webpage
Pharmacovigilance Risk
Assessment Committee (PRAC)
PRAC - Composition
● The PRAC is composed of:
 a chair and a vice chair, elected by serving PRAC
members;
 one member/alternate nominated by each of the 28
Member States;
 one member/alternate nominated by Iceland and by
Norway;
 six independent scientific experts nominated by the
EC;
 one member/alternate to represent healthcare
professionals nominated by the EC;
 one member and one alternate to represent patients
organisations nominated by the EC.
chair
vice chair
June Raine
Almaath Spooner
Source: EMA webpage
Pharmacovigilance Risk
Assessment Committee (PRAC)
PRAC Recommendations – Process Flow
• Referrals
• PSUR Assessment
• PASS Results
Nationally Authorised Products
Centrally Authorised
Products (CAP)
(including MRP & DCP)
PRAC
RECOMMENDATION
Member
States
CHMP
Majority Vote*
Consensus*
OPINION*
* If CHMP/ CMDh recommendations differ from those of the PRAC,
the CHMP/ CMDh shall provide a detailed explanation of the
scientific grounds for the differences with their recommendations.”
Legally
binding
DECISION
to MSs
Source: www.ema.europa.eu
PRAC - Volume of main activities
[July 2012 July 2013]
Number of main agenda topics per
meeting
% of PRAC plenary discussion
time 2013
140
PASS
4%
Other CHMP/MSs
Renewals
4%
120
100
Renewals- Conditional
Renewals- Annual
Reassessments
PASSs
Signal
10%
80
60
PSURs
40
RMPs
20
New Signals
Referrals
33%
Other
14%
PSUR
16%
RMPs
19%
0
New Referrals
Source: PRAC minutes/ 7th EMA stakeholders meeting (June Raine)
Referral procedures
A new pan-European assessment of safety issues
● New referral procedure ‘Urgent Union Procedure’
(107i)
 Automatically assessed at European level
• Triggered by a Member State or the European Commission
 To provide a rapid evaluation of a safety issue linked with
a medicine, regardless of its initial authorisation route of
the medicine
 Scientific assessment lead by PRAC in collaboration with
CHMP and Reference Member State
 Public hearing may be organised depending of the
seriousness of the issue
 Re-examination not possible
 National temporary measures are possible prior PRAC
assessment
 Outcome
• No action, MAH further evaluation, PASS, RMP, Suspension
of MA, Revocation of MA, No renewal of MA
Industry impacts
• Less national specificities/discrepancies
• Learning to cope with public hearing in EU
• Possible immediate temporary measures requested by the
European Commission upon PRAC recommendation -Art. 107(i)
ICSR Reporting and Management
●
Processes for the management of adverse reaction reports need to be re-engineered
and procedures will need to be amended in order to address the new requirements
 New definitions, in particular for
•
Adverse Reaction: A response to a medicinal product which is noxious and unintended.

Includes medication errors and use outside the MA
 Direct patient reporting
 New Reporting arrangements
All EU and non-EU Serious ADRs to Eudravigilance (EV) only within 15 days , including consumer reports
• All EU non-serious reports to EV only within 90 days
•
 EV database is the single point of receipt for expedited reports
•
Until EMA can “ensure the functionalities of EV“ (not before 2015) - Transitional arrangements:

All national non-serious ADRs to Austria (for products under additional monitoring), Croatia, Denmark, Germany (for Vaccines
only), Italy (except literature cases), Poland, and Romania (within 90 days)
 Revised obligations for collecting reports in non-interventional/observational studies
•
All AE (serious or not [for EU at least] in a PV database , to allow reporting of all ADRs.
 Literature monitoring (starting 2015)
•
•
EMA’s monitoring for a list of product in selected scientific literature
MAH’s monitoring for all other medical literature and other products
Industry challenges
• Tracking of off-label use, misuse, abuse, occupational exposure and medication error without AEs
• Collection of non-serious cases in post-authorisation non-interventional studies
Post Authorisation Studies (PAS)
Non-Interventional Studies (NIS)
● Non serious case collection from all PAS: number one concern
 Dir. Article 107(1) :
•
“MAHs shall record all suspected adverse reactions in the Union or in third countries which are
brought to their attention, whether reported spontaneously by patients or healthcare
professionals, or occurring in the context of a post-authorisation study”. GVP Module VI implies only
if actively sought i.e. protocol driven
 Q&A (July 2012) citing GVP Module VI:
•
•
all adverse events should be collected by the MAH and assessed as to whether or not they are
suspected adverse reactions
Applies to all NIS, even if conducted outside Europe
 Significant impact on all non-interventional field studies (NIS) which
become more burdensome regarding AE collection than clinical trials.
 New orientation: proposal of new requirements on management and
reporting of suspected ADR originating in post-authorization studies
•
•
Based on feedback received from practical implementation of requirements set out in module VI
Public consultation on revised text S1 2013 - Still level of draft – final requirements may vary
20
Patient Support Programs (PSP) / Market Research (MR)
● Reports from PSPs / MRs
 All to be classified as solicited in final GVP Module (July 2012), contrary to
what was proposed in the April 2012 draft
 Poorly documented reports; impossible to make informed causality
assessment and attempts to follow up nearly always unsuccessful
 Significant bureaucratic burden with no contribution to patient safety
 Said to be based on FDA position but not consistent with 1997 guidance
● Industry propose to revert to the April 2012 draft guidance
 Clarify the definition and allow classifying into those that actively seek
information and those that do not.
 Actively sought = solicited
 Others = implied causality
 Longer term - collect data to assess impact on signal detection
● Workshop conducted in June 2013 (@)
Signal Detection and Management
● Signal detection in Eudravigilance by the EMA and NCAs (Published and
managed by the PRAC)
● Information on “validated” signals, Emerging Safety Issues and the outcome
of signal assessments should be exchanged between competent authorities
and MAHs.
● Requirements for the MAH
 To track and document all steps of signal detection and management,
 To report to competent authorities validated signal detected from Eudravigilance
(2015) and emerging safety issues such as safety issues arising from the signal
activity which impact B/R balance and/or have an implication for public health
 To monitor Eudravigilance outputs (2015)
Industry challenges
• Surveillance of web portal of National Competent Authority for any new signal posted.
• Integration of the new EV source of signal into signal management process of the company
PRAC - Signal management process
MSs
EMA
MSs
EMA
[MAH]
Signal
detection
List of
confirmed
signals
published
PRAC
n=144
Feb 2014
Validation
Confirmation
(=EPITT)
Analysis /
Prioritization
Assessment
EC
Decision
Recommendation for
action
CHMP/ CMDh
Opinion
Position
Source: www.ema.europa.eu
PRAC - Signal / Recommendations
PRAC Signal
Recommendations
Supply Additional Information
Regulatory Action
centrally authorised
medicines
actionable directly by
the MAHs concerned
CHMP
Endorsement
nationally authorised
medicines
CMDh
Endorsement
MAHs are expected to take action
according to the recommendations
● EMA publications
 PRAC recommendations on safety signals
• MAHs to keep informed about the PRAC recommendations concerning their products.
 A cumulative list of all signals per product discussed at the PRAC since September 2012
Source: EMA webpage – Signal Management
New PSUR / PBRER –
Periodic Benefit Risk Evaluation Report
●
Scope amended
 Analysis of the Benefit –Risk (B/R) balance of a medicinal product with cumulative review of
safety issues, rather than a detailed listing of individual case reports in a period.
 New concept of ICH E2C(R2) implemented in EEA
●
Requirements for PSUR proportional to the risks : Not necessary for low risk products
 Generics/Well-established use products/ Traditional herbal products
●
EU Reference Dates and frequency (EURD) list
 List of substances and combinations of active substances, identify PSURs to be submitted in
accordance with the EURD as determined by the CHMP and CMDh following consultation
with PRAC.
●
Frequency of PSUR/ PBRER specified in the Marketing Authorization or in EURD list
 Variation Required
•
•
in case the PSUR cycle is stated in the MA and to align the MA in line with EURD list
for generics remove a previous standard PSUR statement or to align with EURD list
Industry challenges
• New Benefit sections : Contribution by Medical functions not involved previously
• PSUR/ PBRER Planning and organization strategy was revised globally and locally
EU Renewals
Addendum to Clinical Overview
● Renewal submission at least 9 months before expiry
 Package consolidated quality, safety and efficacy, including all variations
● Request an Addendum to Clinical Overview (ACO) including an Expert
Statement without PSRs* submission
 Final guidelines on renewal process published in Q2/Q4 2012
 Actually content corresponds to a “mini PBRER"
2/21 Jul 2012
Renewal incl. CES+
PSRs* when needed +
Literature ref
Renewal incl. ACO with expert statement
No more PSRs
Literature ref +
Summary of PSMF
RMP when needed
History of PV inspection and summary of non compliance
Industry challenges
• Anticipate the renewal submission package
• New systematic requirement of the ACO has led to formalize the ACO management process
* PSR: considered abbreviation PSR for PSUR, PSUR addendum, Summary Bridging Report and line listing
Post-Authorisation Safety Study (PASS)
● Scope
Any study relating to an authorized medicinal product conducted with the aim of identifying,
characterizing or quantifying a safety hazard, confirming the safety profile of the medicinal product,
or of measuring the effectiveness of risk management measures.
 When imposed by a competent authority :
 As an obligation as part of a marketing authorization or under specific circumstances (well
established products)
 PRAC or to the competent authority of the concerned member state provide


Endorsement/ Objection: Draft protocol /amendment
Recommendation: final study reports and abstracts.
 When voluntarily initiated by a marketing authorization holder including studies proposed
and committed in the Risk management plan (RMP)
Industry challenges
•
•
•
Governance of PASS as new regulatory obligation
Use of new PASS protocol Template. Binding for imposed PASS.
Communication of PASS findings that might influence the Benefit / Risk
Post-Authorisation Efficacy Studies (PAESs)
Objectives
● Studies aimed at determining clinical outcome following initial assessment
based on surrogate endpoints
● Studies on combination with other medicinal products
● Studies in sub-populations
● Studies in the context of the European standard of care
● Studies linked to a change in the understanding of the standard of care for
the disease and/or the pharmacology of the medicinal product
● Studies aimed at determining the long term efficacy of a medicinal product
● Studies in everyday medical practice
Draft Delegated act on PAES
Risk Management Plan (RMP)
● New RMP Template, new requirements
 Obligation to demonstrate the effectiveness of risk minimization measures contained in the
risk management plans
 Key measures of RMP will be included in the Marketing Authorizations (MA) as conditions
with deadlines for the fulfilment
 Publish a summary of RMP in lay language
● Explicit legal basis to request a RMP in an application for Marketing Authorization
 For all new Marketing Authorizations (including generics)
 For authorized products if there are safety concerns
Industry challenges
•
•
•
•
Monitoring of RMPs in all countries
New RMP requirements cause a steep increase in the number of documents
For products without risk management beyond routine: an administrative burden with no
added value?
How to harmonize RMPs for the same substance across all MAHs?

Product Information change:
Additional Monitoring scheme
● List of medicines under additional monitoring – Monthly update since April
2013
 Mandatory
All new active substances (MA from 1-Jan-2011)
• All biological products, including biosimilars (MA after 1-Jan-2011)
•
 Following PRAC recommendation
Authorised products subject to Post Authorisation Study
• Authorised products with conditions or restrictions for the safe and effective use
•
 Medicines will be removed from the list
5 years after Union Reference Date
• or until all conditions are fulfilled
•
● SmPC and PIL statement
 Medicines under additional monitoring
•
“This medicinal product is subject to additional monitoring” preceded by a black symbol()+
standardised explanatory sentence
 For all other medicinal products
• Healthcare professional and patients asked to report any suspected adverse reaction
Industry challenge
• Ensure appropriate update of EU SmPC and EU PIL
MAH Notification of MA events status
Transparency increased
Art 23a (Dir) / Art 13a (Reg) –Art 123 (2) (Dir.) / Art 14b (Reg.)
● Action/ Information related to Registered
medicinal products in the EU
 MA refused, revoked or suspended, withdrawn /
 Supply prohibited / Commercialisation stopped /
 Non Renewal/ B/R re-assessment (new risk &
change in the existing risk)
Grounds Art 116/117(i)
WW
efficacy, negative B/R,
quali-quantitative
composition )
NCA and EMA
Agency / NCA Publications
EMA website : EMA Annual list



+ reasons (e.g. safety,
efficacy, quality, commercial )
National Agencies websites
MAH notification
+ reasons
Other (i.e Commercial)
EU
MA refused, revoked or suspended
Supply prohibited
Commercialisation stopped

NCA or EMA
Industry challenge
• MAHs to devise a Process, challenging for large portfolios
Same information, in national
languages, for the products
registered or marketed in the
country
EU
“Article 57” – xEVMPD
Extended EudraVigilance Medicinal Product Dictionary
● The objective is to better identify the drugs within the ICSRs -Individual Case Safety Reports
 Create a list of all medicines authorised and registered in EU
 Identify medicines accurately, especially medicines included in reports of suspected adverse
reactions
 To improve signal detection accuracy and capabilities
● A number of Data elements/set for medicinal products were required by July 2012.






Product Information
A description of the strength of the active substance(s)
A description of the medical device(s)
The pharmaceutical dose form
The route(s) of administration
An electronic (not a scan) copy, including date of last revision, reference numbers and document
language of SmPC, MAH responsible for batch release
● Maintenance of data to be set up. Mandatory as of June 2014
● Clarification of the language requirements depending on the authorisation procedure :
 National official languages for National Procedures
 English text for CP; English Core European text for MRP/DCP
Industry challenge
• Ensure maintenance and Quality Control ( Up-to-date SmPCs, Inform on any change, Translation,
QPPV information)
Pharmacovigilance System Master file
(PSMF)
● Document describing the company’s PV system
 Replaces the Detailed Description of the Pharmacovigilance System (DDPS)
 Presents the management organisation of the Company PV system from a corporate
perspective including its affiliated entities in respect of the applicable regulatory requirements.
 Includes additional descriptions process (RMP, Safety commitments…) and figures pertaining
to the company portfolio, and results from system audits and Key Performance Indicators.
● Tool for QPPV to maintain oversight with the Pharmacovigilance System in the
company.
● Provision of a soft or a hard copy of the PSMF within a 7 day time-frame if requested
by an authority or at an inspection.
 Supervisory authority for PV is the Competent Authority in which the PSMF is located
● PSMF Summary - Key elements of the Pharmacovigilance System
 To be included in application for any Marketing Authorization (MA), whatever the registration
procedure in module 1.8.1 of the dossier
• at the time of the renewal, or through Type IAIN variation not later than July 2015.
Industry challenges
• Ensure that total PSMF contains current information
• PSMF summary to be associated to each Marketing Authorization
The QPPV role: Regulatory background
European Legislation [DIR Art 104(3)(a)]
● The MAH shall have permanently and continuously at its disposal an
appropriately Qualified Person responsible for PharmacoVigilance” (QPPV) in
the EU.
● The QPPV must be appropriately qualified i.e. adequate knowledge and skills
to manage the PV system as well as expertise/access to expertise in the
following areas:
 Medicine, Pharmaceutical Sciences, Epidemiology, Biostatistics
● If the QPPV does not have basic medical training, access to a medically
trained person must be available and documented in the PSMF.
● The QPPV must reside in the EU [extended to Norway, Iceland or Liechtenstein (EEA)].
● NCA’s have the option to request the nomination of the PV contact person at
national level reporting to the QPPV.
 A contact person at national level may also act as the QPPV.
QPPV oversight =
The QPPV should know everything (1)
Establish and
maintain the MAH’s
PV system
● Have sufficient
authority to influence
the performance of
the quality system
and the PV activities
● Promote, maintain
and improve
compliance with the
legal requirements
To be compliant with legislative requirements
Tools and processes:
● ICSR reporting and submission data
● IT systems (database changes, validation status,
failures during validation etc.)
● aggregate report processes
● SDEAs
● SOP
● Trainings
● Compliance evaluation/reporting (ICSR,
document submission, safety variation –
labelling update etc. – both global + local )
● Quality of data (PBRER, B/R evaluation –
ensuring correctness and completeness of data)
QPPV oversight =
The QPPV should know everything (2)
Products and Processes:
QPPV must have an
overview of the safety
profiles and any
emerging safety
concerns in relation to
the medicinal products
for which the MAH
holds authorisations
● Safety profile of new INNs coming to portfolio
(projects, in-licensing, due diligence)
● Be aware of any conditions or obligations as part of
the MAs and other commitments relating to safety or
the safe use of the products;
● Signal detection and management
● Benefit-risk information
● Risk management and risk minimisation measure
e.g. be aware of the content of RMP
● Be aware of PASS requested by a competent authority
including the results of such studies
● Be involved in the review and sign-off of protocols of PASS
conducted in the EU or pursuant to a RMP
● Risk communication (referrals, Product Alerts, product
withdrawal ….)
QPPV oversight =
The QPPV should know everything (3)
Acting as a single
contact point for
the Competent
Authorities on a 24hour basis
Must be located in
the EEA
● Ensuring response to any request from the CA
and the Agency for the provision of additional
information necessary for B/R evaluation
● Providing any other information relevant to the
benefit-risk evaluation to CA and Agency;
● Providing input into the preparation of
Regulatory action in response to emerging
safety concerns (e.g. variations, urgent safety
restrictions, and communication to patients and
healthcare professionals);
● To be contact point for PV inspections
QPPV oversight =
PV System compliance and quality
Approval/signatures required
● PSMF
● PSUR/PBRER approval
● RMP approval
● PASS approval (QPPV)
Internal audit
● Own system
● Third parties
● External partner audit
PV inspection
● Competent authority
● EMA
CA or EMA/PRAC
negotiation (PBRER,
RMP, PASS, DUS etc.)
Joint studies
Audit plan
Periodic audit
Compliance data
Compliance
CAPA -follow-up
Fees for PharmacoVigilance
●
Legal proposal under discussion since June 2012 between European Commission, European Parliament, Member States
(MS).
 On June 26, 2013 European Commission has adopted a legal proposal (@)
 In February 2014, EU MS have approved a compromise agreement between with the European Parliament on a draft regulation
for establishing the long overdue EU pharmacovigilance fee regime (@)
 The final regulation needs to be approved by the Parliament and council once revised by the lawyer linguist.
●
Agreement on 2 types of fees charged to marketing authorisation holders:
Annual Flat Fee
 €67 per pharmaceutical form (eg tablets, drops and injectables) of medicinal products authorized at national level.
 This fee is intended to cover the costs of general pharmacovigilance activities of the EMA, such as safety data management,
literature monitoring and information technology, notably maintenance of the EudraVigilance database.
Pharmacovigilance Assessment Procedure Fees
 The EMA will charge fees for three pharmacovigilance assessment procedures performed at EU level to marketing authorization
holders (MAHs) that have at least one product involved in such a Union-wide PV procedure:
•
•
•
Assessment of PSUR – €19,500 per procedure, of which €13,100 is for national competent authorities (NCA);
Assessment of PASS – €43,000, of which €18,200 is for NCA; and
Assessments of referrals initiated as a result of PV data – standard fee of €17,9000, which can reach up to
€295,000 in exceptional cases involving five and more active substances.
Sharing of the referral fee revenue between the involved authorities: 1/3 for EMA - 2/3 for NCAs .
 The payment of the fee is divided between the MAHs, with each of them being charged a share of the fee that is proportionate to
their share of products covered by the procedure.

●
●
●
No double charging - Fees paid at EU level covered by the regulation not charged at national level.
Small and medium-sized enterprises : fee reduction of 40% and micro-enterprises: exempted from any fees.
Reductions from the annual flat-rate fee : specific types of medicinal products, (e.g generics.)
Industry challenges
• Anticipated to budget for the PV fees.
Conclusion (1)
● The 2010 EU PV legislation is a massive undertaking for all parties; it
offers opportunities, e.g.:






Focus has shift on benefit / risk balance with PBRER concept
Modular concept for RMP/PSUR
Less PSUR for mature and ‘safe’ products
Focus on signal rather than on ICSR evaluation
Integrated “signal-to-labeling” approach
Major step forward in transparency and stakeholder involvement
● Big step toward harmonised pharmacovigilance processes and product
evaluation throughout EU
 PRAC is central to the EU PV legislation
● …but seems also to generate bureaucracy, e.g.:
 Complexity of the regulatory text corpus does not go toward simplification
 AE reporting requirements in NIS go against the objective to develop real-life
studies; AE reporting requirement in PSP is not reasonable
 PRAC may be overwhelmed by the volume of activity
40
Conclusion (2)
● The concept of risk proportionality is there, but…
 Visible: new PSUR format with a more thoughtful and evaluative
approach, no more PSURs for mature products,
 Blurred: massive production of RMPs, logic of signal management at
PRAC
● The new framework for PV, based on collecting, reporting and
analysing “non-ICSRs” safety events (signals, regulatory
decisions…) is emerging painfully
 Technology and budget constraints: Art 57 – xEVMPD, EMA website,
PSUR repository, new Eudravigilance functionalities, centralisation of
literature safety information…
 No standard process/system for exchange of information regarding
signals (e.g communication MAH  PRAC) and regulatory decisions (art
23)
● Anticipation of Budget increase with PV fees
41
Legislative texts
Basic Legislative Acts
Release Date
Regulation (EU) No 1235/2010
December 2010
corrigendum to Regulation 1235/2010
Regulation (EU) No 1027/2012
November 2012
Directive 2010/84/EU
December 2010
corrigendum to Directive 2010/84/EU
Directive 2012/26/EU
October 2012
available in the 23 official languages of the EU
European Commission Delegated and Implementing Acts
Commission Implementing Regulation (EC) No 520/2012 on the performance of
pharmacovigilance activities provided for in Regulation (EC) No 726/2004 and Directive
2001/83/EC
June 2012
Commission Implementing Regulation (EU) No 198/2013 on the selection of a symbol for
the purpose of identifying medicinal products for human use that are subject to additional
monitoring
March 2013
available in the 23 official languages of the EU
Regulation on fees for pharmacovigilance payable to the European Medicines Agency
– Draft legal proposal
June 2013
Draft Concept paper on delegated act on PAES – Draft – Public consultation closed
Nov12Feb13
Questions and answers
EC - Questions and Answers on transitional arrangements Rev.1
July 2012
EMA - Questions and Answers on practical transitional measures for the implementation of the
pharmacovigilance legislation Rev.3
November 2012
CMDh - Questions & Answers document on the Pharmacovigilance Legislation Rev. 8
Jan 2014
| 42
Good PharmacoVigilance Practices (GVP)
Replace volume 9A
GVP (@)
TITLE
STATUS
Release Date
MODULE I
Pharmacovigilance Systems and their Quality Systems
Final
Jun 2012
MODULE II
Pharmacovigilance System Master File
Final. Rev.1
Apr 2013
MODULE III
Pharmacovigilance Inspections
Final
Dec 2012
MODULE IV
Audits
Final
Dec 2012
MODULE V
Risk Management Systems
Final
Jun 2012
MODULE VI
Management and Reporting of Adverse Reactions to Medicinal Products
Final / (Rev.1- Draft)
Jun 2012 / (Jun 2013)
MODULE VII
Periodic Safety Update Reports
Final Rev.1
Dec 2013
MODULE VIII
Post-Authorisation Safety Studies
Final Rev.1
Apr 2013
Annex to Module VIII
Member States' requirements for transmission of information on non-interventional PASS
Final Rev.1
Apr 2013
MODULE IX
Signal Management
Final
Jun 2012
MODULE X
Additional Monitoring
Final
Apr 2013
MODULE XI
Public Participation in Pharmacovigilance
PC Planned
Q2 2014
MODULE XII
Continuous PV, Ongoing Benefit-Risk Evaluation, Regulatory Action & Planning of Public Communication
PC Planned
Q2 2014
MODULE XIII Cancelled
Incident Management - All topics originally intended covered in this module  to be included in XII.
NA
MODULE XIV
International cooperation
PC planned
Q2 2014
MODULE XV
Safety Communication
Final
Jan 2013
MODULE XVI
Risk-minimisation measures: selection of tools and effectiveness indicators
Final
Feb 2014
ANNEX I
Definitions
Final Rev.2
Jan 2014
ANNEX II
Templates: Direct Healthcare Professional Communication (DHPC)
Final
Jan 2013
ANNEX II
Templates: Cover page of periodic safety update report (PSUR) Rev.1
Final
Apr 2013
ANNEX III
Other Guidance Documents
ANNEX IV
ICH Guidelines for pharmacovigilance
ANNEX V
Abbreviations
Final
Apr 2013
P. I
Vaccines for prophylaxis against infectious diseases
Final
Dec 2013
P. II
Biological medicinal products
PC Planned
Q2 014
|
43
Latest news since last meeting –
GVP module update
•
Final - planned 2014
• Module VI Rev. 1 – ADR
•
Public consultation (PC) - planned 2014
• Module XI - Public participation in pharmacovigilance - Q2
• Module XII - Continuous pharmacovigilance, ongoing benefit-risk evaluation, regulatory action
and planning of public communication - Q2
• Module XIV - International cooperation- Q2
• PII – Biological medicinal products - Q2
|
44
Regulatory and procedural guidelines
ICSR
Release Date
EMA - Reporting requirements of ICSRs applicable to MAHs during the transitional period – Rev.8
Nov 2013
EMA - CHMP Guideline on detection and management of duplicate individual cases and ICSRs
Jun 2012
PSUR/ PBRER
EMA - webpage on EURD and submission of PSURs and updates of List and requirements
EMA - List of EU Reference Dates (EURD list) for PSURs
Monthly update
CMDh - List of substances under PSUR Work Sharing scheme and other substances contained in NAPs with DLP synchronised
Monthly update
EMA - Periodic safety update reports: questions and answers Rev.
Feb. 2014
CMDh - Best Practice Guide for Transitional Arrangements for PSUR Work Sharing Rev.3
Jan 2014
CMDh - Q&A transitional arrangements for PSURs for nationally authorised products Rev.2
Jun 2013
EMA - First information day on periodic safety update reports (PSURs)
Jun 2013
EMA - Template- Request for amendments of or addition of active substances/ combinations of active substances to the EURD list Rev.1
May 2013
EMA - How to submit PSURs for EU Single Assessment of substances contained in both CAPs and NAPs to the EMA
May 2013
EMA - NCA requirements for PSUR submission during the transitional period Rev. 7
Nov 2013
HMA - Changes applied to the PSUR Work Sharing and Synchronisation Lists
Mar 2013
EMA - PSUR assessment based on active substances in both centrally and nationally authorised medicines
Mar 2013
EMA - PSUR Assessment Report template Rev.
July 2013
EMA- CHMP approved ICH guideline E2C (R2)
Dec 2012
ICH - ICH guideline E2C (R2) - Periodic benefit-risk evaluation report (PBRER) – Step 4
Nov 2012
EMA - Timetable Periodic Safety Updated Reports (PSURs) Rev.1
Sep 2012
|
45
EU PV
REFERENCETEXTS
QPPV Office
Version as March 2014
|
46
Regulatory and procedural guidelines
Signal
Release Date
EMA - Signal management web page
EMA - PRAC recommendations on safety signals: monthly overviews
Monthly Update
EMA - List of signals discussed at the PRAC since September 2012
Monthly Update
EMA - Questions & answers on signal management
Oct 2013
EMA - Standard operating procedure for signal management for centrally authorised products
Mar 2013
EMA - List of active substances subject to worksharing for signal management
Nov 2012
EMA - Work instructions Screening electronic reaction monitoring reports (eRMR) for new signals
Sep 2012
RMP
EMA - RMP webpage
EMA - First summary for the public of the risk-management plan (RMP) of a newly authorized medicine
Mar 2014
EMA - Changes to RMPs (RMP Update/ Changes to 'important missing information‘)
Aug 2013
EMA - Guidance on format of the risk-management plan in the European Union – in integrated format Rev. 1
Aug 2013
EMA - Guidance on format of the risk-management plan in the European Union for generics Rev. 1
Aug 2013
EMA - Format for risk-management-plan submissions
Jan 2013
PASS
EMA – PASS webpage
Feb 2014
EMA - Template PRAC assessment report of an non-interventional imposed PASS final study report
Feb 2014
EMA - Guidance for the format and content of the final study reports for non-interventional PASS Rev.1
Aug 2013
EMA - Post-authorisation safety studies: questions and answers
Jul 2013
ENCEPP - Guide on Methodological Standards in Pharmacoepidemiology Rev.2
June 2013
EMA - PRAC Rapporteur PASS protocol assessment report
Dec 2012
EMA - Guidance for the format and content of the protocol of non-interventional PASS
Oct 2012
EMA – Timetable PASS Protocols (CAPs and NAPs)
Jul 2012
|
47
Regulatory and procedural guidelines
xEVMPD
Release date
EMA - Electronic submission of information on medicines webpage
EMA - Documents for electronic submission of information on medicines webpage
Renewal (including Addendum to Clinical Overview)
CMDh - Best Practice Guide On The Processing Of Renewals In The Mutual Recognition And Decentralised Procedures rev. 9
Apr 2013
CMDh - Q&A Renewals
Nov 2012
EMA - Guideline on the processing of renewals in the centralised procedure rev.4
Jul 2012
Additional Monitoring
EMA - Medicines under additional monitoring webpage
EMA - List of medicines under additional monitoring webpage
EMA - List of medicinal products under additional monitoring
Monthly update
EC - Medicines undergoing additional monitoring: Video and leaflet to explain new symbol
Oct 2013
EMA- Implementation plan for the introduction of the new pharmacovigilance legislation requirements into the product information of
centrally approved medicinal Products
Mar 2013
European Medicines Agency updates product information template to label medicines subject to additional monitoring and encourage
adverse-reaction reporting
Mar 2013
QRD
EMA - Quality Review of Documents human product-information annotated template (English) v9
Mar 2013
EMA - Appendix V - ADR reporting details Rev. 4
Jun 2013
|
48
Regulatory and procedural guidelines
Referrals (incl. Urgent Union procedure)
Release date
EMA – Webpage on Referral status per medicinal product
EMA - Template and Explanatory Notes of the letter of representation for Referral procedure under Article 31 of Directive 2001/83/EC
Feb 2014
EMA – Questions and answers: Article 31 pharmacovigilance referral
Feb 2014
EMA- Questions and answers: Urgent Union procedure (Article 107i) Rev.
Feb 2014
EMA - Timetable: Safety referral (Art 107i, urgent Union procedure)
Sep 2012
EMA - SOP Article 107 procedures Pharmacovigilance urgent measures
Jun 2012
Variation
CMDh - Q&A for the submission of variations according to Regulation (EC) 1234/2008 Rev.25
Jan 2014
EMA - Practical questions and answers to support the implementation of the variations guidelines in the centralised procedure Rev. 2
Feb 2014
European Commission -Guideline on the details of the various categories of variations to the terms of marketing authorisations for
medicinal products
May 2013
Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008
Aug 2012
Other Regulatory and Procedural guidance
EMA - Marketing and cessation notification: questions and answers
Oct 2013
EMA - Questions and answers on variations to an existing pharmacovigilance system as described in the DDPS
Aug 2013
EMA - Post-authorisation measures: questions and answers
Jul 2013
EMA - Pharmacovigilance system: questions and answers
Mar 2013
|
49
EMA Information & Communication
Release Date
PRAC
EMA - PRAC webpage
PRAC - Draft agenda, highlights and minutes of meetings
Monthly update
PRAC - Rules of Procedure
Mar 2013
PRAC - Elects chair and vice-chair
Sep 2012
PRAC - Countdown to July 2012
July 2012
Commission Decision appointing independent scientific experts to the PRAC
Official Journal of the EU, 23 official languages of the EU
June 2012
CMDh
CMDh - Draft agenda, minutes meetings
Monthly update
Medication Error
EMA – Medication Error webpage
Tackling medication errors: European Medicines Agency workshop calls for coordinated EU approach
Mar 2013
EMA - Position paper on potential medication errors in the context of B-R balance and risk minimisation measures – PC closed
Jun-Nov 2012
Workshops
EMA- Workshop on methods for efficacy studies in everyday medical practice
Oct 2013
EMA - EMA explores ways to further involve patients in the benefit-risk assessment of medicines
Sep 2013
EMA - Workshop on patient-support programmes (PSPs) and market-research programmes (MSP) –
Jun 2013
Transparency
EMA Stakeholder meetings: 2010 pharmacovigilance legislation
Sep 2013
EMA - Transparency: questions and answers
Mar 2013
EMA boosts EU transparency with online publication of suspected side effect reports
May-June 2012
in 23 EU official languages
Fees
European Commission- Concept Paper on the introduction of Fees to be charged by the EMA for Pharmacovigilance - Outcomes of PC
JunJul 2012
European Commission- Proposal for a Regulation Of The European Parliament and of The Council Expected
Jun 2013
| 50
EU PL - Major Regulatory Milestones
PRAC
Implementation
PRAC inaugural
Meeting 19 July
2/21 Jul 2012
PRAC Meeting
3-5 September
PRAC Monthly
Meeting
New CTD
Renewal when required
Nov. 2012
Dec. 2012 10 Jan 2013
Jun 2013 Oct 2013
EV functionalities implementation +
6 months
2015
Transparency and Communication of EMA/NCA/MAH
XEVMPD
associated to ICSR submission
DDPS
PSMF
Audit strategy/ Inspection Readiness
Audit strategy/ Inspection Readiness Readjustment
PBRER format Preparation
New PSUR format Submission / PBRER
ADR management and reporting (ICSR submission – Interim Arrangements)
Signal detection and management
Preparation of new RMP
format
PASS study protocol, abstract, study report : no
strong format
Direct ICSR (incl.non serious )
submission to EV
+ MAH EV monitoring
Submission of new RMP format
Effectiveness of Risk minimisation measures
PASS study protocol abstract, study report new format
PAES
Products subject
monitoring
Products
subjecttotoadditional
additional
monitoring
+ Monitor List
|
51