kom (2016) 0498 - Ingen titel

Europaudvalget 2016
KOM (2016) 0498
Offentligt

EUROPEAN

COMMISSION

Brussels, 8.8.2016

SWD(2016) 284 final

COMMISSION STAFF WORKING DOCUMENT

Accompanying the document

Commission Report

Pharmacovigilance related activities of Member States and

the European Medicines Agency concerning medicinal products for human use

(2012 – 2014)

{COM(2016) 498 final}

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XECUTIVE SUMMARY



The European Union (EU) Member States, the European Medicines Agency (EMA), and the

European Commission work together in a network to support safe and effective use of

medicines by patients and healthcare professionals. Safety of medicines is monitored and

assessed continuously after marketing.

New European legislation which came into operation in mid-2012 has been designed to build

on and enhance pharmacovigilance in the EU. The

new legislation

has built on existing

activities and structures and brought new tools which allow regulators better ways to

proactively optimise safe and efficacious use of medicines for the benefit of EU citizens.

A new EU-level expert committee, the

Pharmacovigilance Risk Assessment Committee

(PRAC), brings together Member State and other experts and patient and healthcare

professional representatives, to share effort and best available expertise in many key

pharmacovigilance tasks.

This report describes the development of the system over the period from July 2012 (when

the new legislation came into operation) to June 2015, with data collected to the end of

December 2014. Some of its key findings are:



Side-effect reporting

has improved, with reporting of suspected adverse reactions

from the European Economic Area (EEA) increasing from around 240,000 in 2012 to

nearly 290,000 in 2014.



all Member States have implemented measures to allow and encourage patients to

report side effects as well as healthcare professionals; this strengthened patient

involvement is shown by an increase of around 50% in individual patient reports.



Member States and the EMA are contributing collaboratively to the detection and

validation of

signals

(information about new or changing safety issues potentially caused

by a medicine); nearly 200 such signals were assessed by the PRAC during the period of

the report. About half of confirmed signals led to updates of the product information, and

a further quarter to other regulatory measures.



The safety of medicines is increasingly being managed proactively through

risk

management plans.

These identify known and potential risks of marketed medicines and

the measures planned to manage them, as well as detailing binding commitments on how

they will be monitored for safety and actions to be taken to provide evidence where it is

lacking.



The PRAC is now assessing around 600 risk management plans each year for

centrally authorised medicines, while over the period of the report some 20,000 risk

management plans have been submitted to the Member States for nationally authorised

medicines; and publication of public summaries of risk management plans has been

trialled.



During the reporting period discussion of the protocols (study designs) for

post-

authorisation safety studies

were included in the PRAC agenda on over 230 occasions,

and results of such studies were discussed on around 60 occasions. In addition, since the

introduction of the relevant legislation some 14

post-authorisation efficacy

studies have

been imposed by the regulator. Member States assessed a further 17 safety studies and

one efficacy study.



kom (2016) 0498 - Ingen titel



Regular re-assessment of the benefit-risk balance of marketed medicines is being carried

out via submission of

periodic safety update reports

(PSURs) for assessment by

regulators. Member States evaluated over 12,000 PSURs for purely nationally authorised

medicines. In addition, the PRAC reviewed and finalised over 900 assessments for

centrally authorised medicines, or for active substances used in both centrally and

nationally authorised medicines. From the last quarter of 2014 all nationally authorised

medicines containing substances listed in the EU Reference Date (EURD) list will have a

periodic safety update report single assessment (PSUSA) reviewed by the PRAC and the

number of procedures through the PRAC for substances only included in nationally

authorised medicines increased significantly in 2015.



There were 31

safety-related referrals

to the PRAC during the period. The revised

legislation has improved the efficiency of the referral procedure, with greater involvement

of patients and other key stakeholders in the process, and improvement in the

identification of key evidence for assessment, with outcomes communicated clearly and

appropriately.



Around 200

pharmacovigilance inspections

have been carried out yearly (167 in 2014)

and the proportion of these related to centrally authorised medicines increased over the

period from 26 in 2012 to 48 in 2014. It is routine practice for a copy of the

pharmacovigilance master file and logbook to be requested in all inspections by the

regulatory authorities.



A clearer focus on

medication errors

is expected to help reduce associated harms. Side-

effect reports related to medication errors increased from around 4,500 in 2012 to over

7,000 in 2014, in part because of increased awareness and a clearer legal basis. Member

States and the EMA have used various channels to communicate about the risks of

medication errors, and in 2013 were involved with key stakeholders in a major workshop

to develop an EU action plan to complement the various national activities already being

carried out.



The activity and performance measures relating to the EU pharmacovigilance system,

particularly for signals, PSURs and referrals suggest that the new system delivers faster

detection of safety issues and faster advice and warnings to users of medicines. Through

faster warnings,

patients and healthcare professionals are empowered to use medicines more

safely.

The EU pharmacovigilance system now provides an unprecedented level of

transparency,

with prompt

communication

to the public on safety concerns regarding medicines as they are

investigated and managed. There is public access to the agendas and minutes of the PRAC,

outcomes of signals and PSURs, and aggregated data on suspected side effects. An early-

notification system (ENS) and circulation of agreed lines-to-take help ensure that messages

are co-ordinated and consistent across the EU regulatory network.

The focus on

engaging patients and healthcare professionals

is a key pillar of the new

legislation. Patients and healthcare professionals report suspected side effects, contribute to

the decision-making process and add the invaluable perspective of those most affected by

diseases and their treatment.

The EU pharmacovigilance system has

improved co-ordination and collaboration

between

regulators and other stakeholders, including academia and industry, and has developed an

enhanced infrastructure to support its new tasks.



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

The extensive work over the reporting period and the experience gained gives a solid

foundation to further

develop and streamline

the system in coming years.

This document builds on the one-year report on the European Medicines Agency human

medicines pharmacovigilance tasks published in May 2014

, which covered the reporting period

July 2012 to July 2013 and described the initial implementation of the revised pharmacovigilance

legislation with a particular focus on the tasks of the EMA.

This report provides data on key pharmacovigilance tasks over a three-year period (including

quantitative data from July 2012 to December 2014) and importantly, given their major

contribution, includes Member State tasks. In addition the report provides evidence of the

continuing development and improvement of the system as regulators and other stakeholders

have gained experience in the use of the tools the legislation provides. It also includes some

information on ongoing developments and anticipated future elaborations of the system.

While certain impacts of the tasks of pharmacovigilance are highlighted in this report, it does not

attempt to provide a comprehensive impact assessment.

European Medicines Agency. One-year report on human pharmacovigilance tasks by the European Medicines

Agency:

http://ec.europa.eu/health/files/pharmacovigilance/2014_ema_oneyear_pharmacov_en.pdf.

kom (2016) 0498 - Ingen titel

NTRODUCTION

This report describes the activities of the networked and collaborative system for monitoring and

controlling the safety of human medicines in the EU over a period covering three years following

the start of operation of new European legislation designed to improve that system.

While the legislation foresees different timelines for reports on tasks of the Member State and of

the EMA, reporting on the EMA tasks has been brought forward for this report in order to allow a

joined-up overview of the tasks of the EU network.

This report specifically includes quantitative data gathered over the period from July 2012 to

December 2014 (the data lock point), but includes information on some relevant tasks and

processes over the whole 3-year period up to July 2015. The body of the report gives a summary

of the activities with technical data provided in full in annexes. It contains a high-level

description of the EU pharmacovigilance system (the system for monitoring and maintaining the

safety of medicines in Europe), the roles of various parties within that system, key activities

undertaken by the system during the reporting period, discussion of the co-operation between

various stakeholders and interested parties, and consideration of the ways in which the system is

being developed and adapted for future improvement.

HARMACOVIGILANCE IN THE

UROPEAN

NION

(EU)

What is pharmacovigilance?

Pharmacovigilance

planned monitoring of the safety of medicines

so that

anything that affects their safety profile can be swiftly detected, assessed, and

understood and appropriate measures can be taken to manage the issue and assure

public health.

Before a medicine is authorised for use, evidence of its safety and efficacy is usually limited to

the results from clinical trials. This means that at the time of a medicine’s authorisation, it will

only have been tested in a relatively small number of patients for a limited length of time.

Some side effects or 'adverse reactions' may only be seen in patients with particular

characteristics or may be so rare that they are not seen until a very large number of people have

received the medicine and used it over longer time periods. This can only happen once healthcare

professionals begin prescribing. It is therefore vital that the safety of all medicines is monitored

throughout their use in healthcare practice. This monitoring applies both to the hundreds of

centrally authorised medicines

(CAPs, those with a single marketing authorisation adopted by

the Commission which is valid across the EU on the basis of an evaluation by the EMA) and to

the many thousands of

nationally authorised medicines

(NAPs, authorised in particular Member

States following national evaluation procedures including the mutual recognition and

decentralised procedures).

The EU network

Over the years the EU Member States have developed systems for monitoring the safety of

medicines on their markets. EU legislation has gradually built on their best practice to create a

networked system that joins the knowledge and resources of the Member States together, co-

ordinated and supported by the EMA, with the European Commission providing the legal

authority and legislative tools that the system requires.

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Regulatory context

The legislation

The legal framework of pharmacovigilance for medicines for human use marketed within the EU

is provided for in Regulation (EC) No 726/2004

and in Directive 2001/83/EC

, as amended.

These were updated by the new pharmacovigilance legislation contained in Regulation (EU) No

1235/2010

and Directive 2010/84/EU

, which entered into force from July 2012 and were further

refined by Regulation (EU) No 1027/2012

and Directive 2012/26/EU

which provided

strengthened measures for monitoring medicines safety and carrying out reviews at a European

level.

In addition in 2012 the Commission Implementing Regulation (EU) No 520/2012

laid down the

rules concerning the roles and responsibilities regarding certain aspects of pharmacovigilance for

marketing authorisation holders, national competent authorities and the EMA.

Member States and the EMA have also produced, in consultation with relevant stakeholders,

good pharmacovigilance practice guidelines (GVP)

which explain in detail how

pharmacovigilance activities should be carried out.

The role of the Member States

The individual Member States of the EU power the entire system. The national medicines

regulators (national

competent authorities)

supervise the collection of information on suspected

side-effects of medicines, particularly spontaneous reports from patients and healthcare

professionals. Equally, they provide much of the resource base and knowledge needed to assess

signals of possible emerging side effects. Member State experts also take the lead (as the so-

called rapporteur and co-rapporteur teams) in evaluating and analysing data when a safety issue is

assessed at the European level (a referral). They play a critical role in tailoring and

communicating safety messages to healthcare professionals, patients and the public at a national

level.

Member States also maintain the inspectorates that carry out the work of ensuring that medicines

marketed in the EU are manufactured appropriately and are of suitable quality, that the

pharmacovigilance systems of industry are working as they should, and which check that the

Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down

Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and

establishing a European Medicines Agency, OJ L 136, 30.4.2004, p. 1.

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code

relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67.

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, OJ L 348, 31.12.2010, p.1.

Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards

pharmacovigilance, Directive 2001/83/EC of the European Parliament and of the Council on the Community code

relating to medicinal products for human use, OJ L 348, 31.12.2010, p. 74.

Regulation (EU) No 1027/2012 of the European Parliament and of the Council of 25 October 2012 amending

Directive 2001/83/EC as regards pharmacovigilance, OJ L 316, 14.11.2012, p. 38.

Directive 2012/26/EU of the European Parliament and of the Council of 25 October 2012 amending, as regards

pharmacovigilance, Directive 2001/83/EC, OJ L 299, 27.10.2012, p.1.

Commission Implementing Regulation (EU) No 520/2012 of 19 June 2012 on the performance of

pharmacovigilance activities provided for in Regulation (EC) No 726/2004 of the European Parliament and of the

Council and Directive 2001/83/EC of the European Parliament and of the Council, OJ L 159, 20.6.2012, 0.5.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000345.jsp

kom (2016) 0498 - Ingen titel

clinical studies that provide the evidence of the safety and effectiveness of medicines are

performed in line with appropriate standards.

The role of the European Medicines Agency (EMA)

The EMA has a central role the EU system, co-ordinating its activities and providing technical,

regulatory and scientific support to the Member States and industry. It also provides essential

infrastructure required by the system and has specific tasks laid down in the legislation in the

conduct of pharmacovigilance including signal detection for centrally authorised products.

The new EU pharmacovigilance legislation established an additional scientific committee, the

Pharmacovigilance Risk Assessment Committee

(PRAC), whose members include experts in

pharmacovigilance and regulation working within the national competent authorities of the

Member States (plus Iceland and Norway), representatives of patients and healthcare

professionals, and scientific experts in areas such as epidemiology, signal detection, biological

medicines and risk communication nominated by the European Commission. The PRAC meets

monthly and is responsible for the assessment of safety issues at EU level. It also monitors many

of the pharmacovigilance activities foreseen in the legislation. It works closely with other

scientific committees, especially the Committee for Medicinal Products for Human Use (CHMP)

which leads on centrally authorised medicines, and also with the Co-ordination Group for Mutual

Recognition and Decentralised Procedures – Human (CMDh), a body representing the national

regulators of the EEA, which leads on many issues relating to nationally authorised medicines.

The staff of EMA develop and maintain various essential databases and information technology

(IT) functions that support the system, in particular a database called

EudraVigilance

that is used

to collate worldwide reports of suspected side effects (adverse reactions) and underpins the

detection of potential signals regarding side effects and their analysis. The EMA also supplies

specialist scientific, legal and regulatory knowledge to support activities such as safety reviews,

and helps ensure that communications about safety issues are provided in a timely, transparent

and co-ordinated fashion across the EU.

The role of the Commission

The European Commission is the competent authority for centrally authorised products and

supplies the legal authority that underpins the EU pharmacovigilance system. It provides the

legislative framework needed to carry out its functions in the most efficient way.

Tasks and procedures

Key tasks carried out by the network for the purpose of pharmacovigilance include:



assessing the known and potential risks of each medicine before marketing and developing

plans to collect data and minimise those risks (risk management planning);

collecting and managing case reports of possible side effects (adverse drug reactions);

analysing reports of side effects to identify signals (signal management);

routine benefit-risk monitoring of medicines via periodic safety update reports (PSURs) and

maintaining the EU Reference Date (EURD) list of when they should be submitted;

managing information on products which are subject to additional monitoring, and products

that have been withdrawn;

Europe-wide reviews of important safety and benefit-risk issues (referrals);

assessing and co-ordinating studies after marketing (post-authorisation safety studies, post-

authorisation efficacy studies);



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

carrying out inspections to ensure company pharmacovigilance systems comply with good

pharmacovigilance practice;

communicating in a clear, effective and timely manner about safety-related issues to relevant

stakeholders;

continuous development and improvement of systems (including IT infrastructure), guidelines

and standards for the system, and promotion of research to address gaps in knowledge;

interacting with and engaging key stakeholders, including patients, healthcare professionals,

the pharmaceutical industry, other parts of the regulatory system (including international

regulators), academia, the media, global standards bodies, and wider civil society;

monitoring the performance of the system and its components, including compliance with

legal obligations and standards;

training and capacity building.



OURCES OF DATA

Information regarding Member State activities has been supplied by the national competent

authorities of the different countries (see

Annex 10),

and includes data from the SCOPE project

funded as a Joint Action by the European Commission and co-ordinated by the UK Medicines

and Healthcare products Regulatory Agency (MHRA). Data on centralised activities, particularly

those carried out by the PRAC and some other areas such as side-effect reporting, has been

collected by the EMA in its co-ordinating role within the EU network.

Qualitative information, including some descriptive case studies, is included in the report in order

to illustrate the way the legislation works at the level of individual issues and to demonstrate the

experiences of stakeholders.

How was it measured/analysed?

The quantitative data for the report covers the period from July 2012 to December 2014 (the data

lock point). Measures of relevant tasks are provided using a variety of indicators. Some represent

basic activity measurements, e.g. simple counts of numbers of procedures or submissions. Others

have been used as part of the pharmacovigilance system governance by the EMA, including key

performance indicators, which have been specifically developed to measure how well it is

carrying out its tasks and to reflect specific outputs required by the new legislation.

Strengthening Collaboration for Operating Pharmacovigilance in Europe, an EU-funded Joint Action project

involving regulators from 23 EU Member States plus Norway and Iceland.

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VERVIEW OF KEY ACTIVITIES

A number of key pharmacovigilance activities over the period from July 2012 to December 2014

(the data lock point), or in some cases over the whole 3-year period up to July 2015, are described

in more detail in the following sections.

Since establishment of the PRAC by the new legislation, the EU pharmacovigilance network

carries out many of these activities in this forum, allowing broad access to expertise and a

consistent and resource-efficient approach to medicines safety across the EU. The relative

frequency with which various pharmacovigilance activities appear on the PRAC agenda is

indicated by the figures below (see

also

Annex 9).

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Side effect reporting

see also

Annex 1

Reports of suspected side effects (adverse

reactions)

submitted by patients and

healthcare professionals are collected by the national competent authorities of the

Member States or by industry. EU law requires all

serious adverse reactions

occurring in the EEA to be included in the EudraVigilance database by the Member

States and marketing authorisation holders. The latter are also required to include

serious reports gathered outside the EEA in EudraVigilance. An

ICSR

(individual

case safety report)

is the standardised format used by regulators for reports of

suspected adverse reactions (side effects) or problems with the safety and quality of

medicines.

The number of serious adverse reactions (SARs) received by EudraVigilance (EV) has been used

as the measure of adverse drug reaction (ADR) reporting. Reports of ADRs following the

authorisation of medicines (i.e. postmarketing) from the EEA have increased steadily following

the implementation of the new legislation, from around 240 000 in 2012 to nearly 290 000 in

2014. There has also been an increase in similar reports from outside the EEA.

One of the aims of the legislation was to

strengthen patient involvement

in the safety

monitoring of medicines. All 28 Member States have patient reporting systems in place, with the

majority introducing them in 2012/13 (although the first of them to introduce this process did so

in 1968 and the second in 1996). Overall, the number of individual patient reports from the EEA

has increased over the two and a half years of the reporting period by around 50%. This includes

ADR reports not notified by other reporters such as healthcare professionals, which represent

information that would not otherwise be captured

Data on national activities in this area has been obtained from a survey of the Member States

carried out via the SCOPE Joint Action. In 24 Member States patients can report via mail, in 21

via e-mail, 20 through fax and web-based forms, and in 19 via telephone. One also specified

mobile reporting, and 2 others that patients can report in person. Most (22) Member States have

more than one type of reporting form, with the majority having 2 different types of forms for

different users (such as patients and healthcare professionals).

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The Member States make patient reporting forms available through a variety of sources; the most

common source, aside from national competent authorities, are regional centres (8 Member

States), patient organisations (7), marketing authorisation holders (7) and healthcare websites (6).

In addition paper forms are made available via pharmacies in 7 Member States.

The single most important tool for encouraging side-effect reporting is institutional webpages.

However, 23 Member States also use educational material and letters for healthcare professionals,

and 20 Member States make information publicly available in annual reports.

In addition, nearly a third (28%) of Member States engage with the media (through advertising

hoardings, radio, television, internet, newspapers) in side-effect reporting campaigns.

Engagement via regional centres, e-learning platforms, and social media like Facebook and

Twitter (in 4 Member States) is less frequent.

The majority (64%) of Member States have a strategy in place to raise awareness about reporting,

although only a third of the countries have a specific budget dedicated to raising awareness.

About 40% of Member States have organised a public campaign about reporting side effects,

with 62 campaigns in total across all the countries. During campaigns, Member States primarily

collaborate with healthcare professional organisations, and to a lesser extent with patient

organisations. Campaigns have focussed on a number of areas, the top three being: the

importance of reporting; content of reports; and, highlighting the schemes in place for reporting.

Some Member States work with patient organisations to facilitate side effect reporting. The

number of patient organisations involved per Member State varies from 1 to 20. For example, in

Denmark the regulator holds meetings with all major patient organisations.

The Member States, the EMA and marketing authorisation holders work collaboratively to

improve the quality

of suspected ADR reports. This includes the use of technology to support

reporting (e.g. web forms), training, quality review and feedback, follow-up with reporters and

detection and amalgamation of duplicate reports. During 2013 and 2014, over 250 000 potential

duplicate couples of case reports were assessed and approximately 110 000 merged ‘master’

ICSRs were created.

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Suspected side effects due to biological medicinal products

EU legislation requires Member States to clearly identify so-called biological medicinal products

(medicines that contain one or more active substances made by or derived from a biological

source) that are associated with suspected adverse reactions. These active substances are larger

and more complex than those of nonbiological medicines, and their complexity and the way they

are produced may result in small variations in the molecule, especially between different brands

and also between batches of the same brand.

The numbers of ICSRs received for biological centrally authorised products over the period

increased slightly from around 34 500 in July-December 2012, 73 000 in 2013 and 77 500 in

2014. Most Member States require the batch/brand in reporting forms, and if not present, will

generally follow up with the reporter.

Signals

see also

Annex 2

A safety

signal

is information on a new or known adverse event that is potentially

caused by a medicine and that warrants further investigation. Signals may be

generated from any information source but most come from ICSRs, clinical studies

or the scientific literature. This information undergoes an initial examination to

determine that it can be considered a possible signal (validation), before being

confirmed as a possible signal for evaluation by the PRAC and regulatory action if

necessary.

The work of detecting signals is shared between the Member States and the EMA. Since July

2012, revised signal detection processes have been put in place for all centrally authorised

medicines. For active substances in nationally authorised medicines, Member States have shared

between them the task of monitoring new data and validating and confirming signals on behalf of

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the rest of the EU system, with EMA supporting them in applying the new signal detection

processes. Each country may be Lead Member State (LMS) for a number of active substances.

This allows the different Member States to contribute according to their resources and permits

more efficient use of those resources by avoiding duplication and clearly defining

responsibilities.

Some 193 unique signals were evaluated by the PRAC over the period of this report. The work of

validation was shared more or less evenly between the Member States and the EMA.

Over two-thirds of signals are for substances found in centrally authorised products, or in both

centrally and nationally authorised products, which would include the great majority of new

active substances entering the EU market.

Validated by NCAs as LMS = reviewed by the lead Member State (the Member State taking the

lead on a given active substance); validated by NCAs = reviewed by another Member State;

validated by EMA = reviewed by the European Medicines Agency

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After a signal is evaluated by the PRAC, it may result in an update of the product information for

the medicine(s) concerned – for example, to add a warning or mention a new side effect, or to

update information on the frequency of a known one – or the regulatory authorities may require

the manufacturer to carry out further study, or put in place additional measures to minimise any

risk. A list of signal recommendations is published after each meeting of the PRAC

Over the reporting period and up to the start of 2015, about half of all confirmed signals

evaluated by the PRAC resulted in recommendations to update the product information (PI) used

by doctors and patients, and a further quarter to other routine pharmacovigilance measures such

as changes to frequency or content of periodic safety update reports, while about 1 in 20 led to

more intensive action in the form of a European-level safety review or ‘referral’.

The functioning of the signal assessment process under the legislation can be illustrated by two

case studies, one representing a signal picked up by routine signal monitoring activities at the

EMA and one a signal first identified by a Member State.

Case study: Filgrastim and pegfilgrastim (Neulasta and other products) – signal of systemic

capillary leak syndrome and cytokine release syndrome

What was the signal and what evidence supported it?

Filgrastim, or its modified, longer-acting version pegfilgrastim, are substances similar to a natural

protein called granulocyte colony-stimulating factor (G-CSF) which encourages the bone marrow

to produce more white blood cells. They are used under various names, representing both

centrally and nationally authorised products, to help reverse a shortage of white blood cells

(neutropenia) that can be caused by cancer chemotherapy and which leaves patients vulnerable to

infection.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000375.jsp&mi

d=WC0b01ac0580727d1c

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In 2012, routine signal monitoring activities by the EMA identified 15 cases of two potentially

life-threatening conditions, systemic capillary leak syndrome and cytokine release syndrome, in

patients treated with these medicines. After discussion with the rapporteur for the centrally

authorised pegfilgrastim product Neulasta, the PRAC was requested in December 2012 to assess

the signal.

How was it evaluated?

The PRAC agreed the signal needed further investigation and noted that the two conditions might

be hard to distinguish. It asked the company holding the marketing authorisation to systematically

review the scientific literature and provide within 60 days an analysis of all reports of either

condition in patients receiving filgrastim or pegfilgrastim for assessment by the rapporteur (UK).

On the basis of this assessment and the PRAC discussion the Committee considered that there

was fairly strong evidence that systemic capillary leak syndrome was associated with treatment

with filgrastim or pegfilgrastim, and that given the potential seriousness of the condition there

was a need to inform prescribers of the risk. The evidence for a link with cytokine release

syndrome was more limited, but needed to be kept under review.

What action was taken?

As a result of its evaluation, in March 2013 the PRAC recommended



the update of the product information (for both centrally and nationally authorised

products) within 30 days to include a warning of the potential risks;

the preparation of a letter for healthcare professionals explaining the changes to the

product information and the possible risks of the condition;

the update of the risk management plan to include systemic capillary leak syndrome as an

important identified risk and cytokine release syndrome as a potential risk, with

appropriate ongoing monitoring.

Conclusions

The system enables effective detection of new side effects and rapid action to manage them.

Case study: Basiliximab (Simulect) – signal of cardiovascular instability resulting in fatal

outcome associated with off-label use in cardiac transplantation

What was the signal and what evidence supported it?

Basiliximab (Simulect) is a centrally authorised medicine approved for use as part of combination

treatment to prevent rejection of a transplanted kidney. It contains the active substance

basiliximab, an antibody that reduces proliferation of activated T-lymphocytes, a type of white

blood cells that play a major role in rejection of a transplanted organ.

In 2013 the Swedish Medicines Agency identified 3 cases of patients who had died when

basiliximab was used outside its approved uses (off-label) to help prevent rejection of a

transplanted heart rather than a kidney. A search in EudraVigilance also identified cases of heart

failure and cardiac arrest in patients who had been given basiliximab for its approved indication.

Sweden requested that the PRAC assess the signal.

Pharmacovigilance Risk Assessment Committee. Minutes of 4-7 March 2013 meeting. Available at:

http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2013/04/WC500142504.pdf.

kom (2016) 0498 - Ingen titel

How was it evaluated?

The PRAC agreed that the signal needed further investigation. It asked the company holding the

marketing authorisation for an initial analysis of all cases describing events due to clots

obstructing blood vessels (thromboembolic events), disorders of heart rhythm (arrhythmia,

bradycardia), or heart failure. Subsequently it requested further analysis of effects on the heart

and data from studies in heart transplantation.

The PRAC found that data from studies in renal transplantation and from the literature were

reassuring when the medicine was used for its authorised indication. However, although the

evidence did not show a strong signal of increased heart risk in patients undergoing heart

transplantation, data from 6 clinical trials which were examined did not indicate benefit in these

patients.

What action was taken?

As a result of its evaluation, the PRAC recommended that



the product information be updated within 60 days, to include a warning about use in

heart transplantation, advising healthcare professionals that benefit had not been

demonstrated and that serious effects on the heart had been reported more often than with

other anti-rejection medicines;

a letter be sent to remind heart surgeons and doctors in heart transplant centres in the EU

that basiliximab is only approved for use in kidney transplantation;

the risks of effects on the heart be included in the risk management plan for the product

and to be included in regular ongoing safety monitoring (PSURs).



Conclusions

Signal evaluation by the PRAC offers a new instrument for early interventions on safety issues,

increasing the flexibility present in the system and improving its response time.

Risk management plans

see also

Annex 3

Every medicine approved for marketing in the EU is now required to include a

Risk

Management Plan

(RMP) as part of the dossier submitted by the company. The

plan identifies known and potential safety issues with the medicine, and includes

binding commitments on how the medicine will be monitored for safety during its

lifetime. It also identifies the actions that will be taken to minimise the risks and

provide evidence where it is lacking, so as to ensure the most favourable balance of

risks against the medicine’s benefits.

Risk management plans for centrally authorised medicines are reviewed by the

PRAC, with initial detailed evaluation by assessors in the Member States who take

the lead in evaluating the medicine, and approved by the CHMP. RMPs for

nationally authorised medicines are evaluated at Member State level with

consultation of the PRAC only at the request of a Member State.

Pharmacovigilance Risk Assessment Committee. Minutes of 3-6 February 2014 meeting. Available at:

http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2014/03/WC500163384.pdf.

kom (2016) 0498 - Ingen titel

Risk management plans represent an important part of the move to proactive pharmacovigilance.

Every new medicine and significant extension of indication approved during the reporting period

has a risk management plan, meaning that a binding plan for risk minimisation and further study,

as envisaged by the legislation, is in place for these products.

There were 48 RMP assessments handled by the PRAC during June-December 2012, 637 in 2013

and 597 in 2014, representing about 20% of the discussion time in the meetings of the PRAC.

During the same period, around 3 500, 7 500, and 9 000 RMPs respectively were submitted to the

Member States for nationally authorised medicines.

RMPs submitted to NCAs

10 000

8 000

6 000

4 000

2 000

2012 Jul-Dec

2013

2014

kom (2016) 0498 - Ingen titel

The complete risk management plan is a very lengthy technical document, and is not published in

full. However, public assessment reports are required to be published for all marketing

authorisations for new medicines and significant extensions of indication for existing medicines,

and these include discussion of the safety and relevant risk management aspects. To further

increase transparency and, as required by the updated legislation, to provide information on

RMPs to the public, a pilot of the publication of summaries of the RMP plan was carried out in

2014. For further details, see the section on Communications and Transparency, below.

Periodic safety update reports

see also

Annex 4

European legislation requires marketing authorisation holders to submit regular reports

providing an evaluation of the benefit-risk balance of a medicine. These periodic

benefit-risk evaluation reports (PBRERs), known as

periodic safety update reports

(PSURs), must be submitted for both centrally and nationally authorised medicines at

defined time points following a medicine’s authorisation. They include the results of

studies carried out with the medicine, as well as any other new information on safety or

benefits, and cover both authorised and unauthorised uses.

The information is reviewed by the PRAC to determine if there are new risks identified

for a medicine or whether the balance of benefits and risks of a medicine has changed.

If it has not, then the marketing authorisation can be maintained, but the PRAC can also

decide if further investigations need to be carried out or can take action to protect the

public from any new risks identified, such as updating the information provided for

healthcare professionals and patients through a variation, or potentially even suspending

kom (2016) 0498 - Ingen titel

or revoking the authorisation. A list of dates for submission of PSURs (the EURD list)

is made available on the EMA website

A single assessment of related PSURs (known as a

PSUSA)

is carried out for medicines

that contain the same active substance or combination of active substances and whose

assessment period has been synchronised. This allows for more efficient use of

resources and also ensures that these related medicines are evaluated in a consistent

way.

The regular re-assessment of benefit-risk represented by the PSURs is a fundamental part of

ensuring the safe use of medicines for EU citizens; it ensures that the benefit-risk balance is

regularly monitored, with appropriate action where needed, but also allows the regulatory burden

to be proportionate to the risks, with more frequent assessments where the PRAC deems

necessary, for example for newer medicines.

The number of PSURs reviewed by the PRAC was 20 during the starting period of July-

December 2012 relating to active substances that were contained in only centrally authorised

medicines, but increased to 436 in 2013 and 471 in 2014 as the scope of the PRAC’s assessments

was broadened to PSUR single assessments (PSUSA) for active substances contained in both

centrally and nationally authorised medicines. In most cases the marketing authorisations were

maintained unchanged, but around 1 in 5 of the PSUR assessments during the reporting period

resulted in variations to the terms of the authorisation resulting in changes such as updates of the

product information to improve information on side effects or precautions when using the

medicine.

The number of PSURs additionally submitted to national competent authorities in the Member

States for purely national assessments were around 5 000, 3 700 and 3 300 for the same periods.

PSUR assessments and PSUSA

finalised per year

500

400

300

200

100

430

426

Jul-Dec 2012

2013

CAPs only

2014

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/10/WC500133159.xls

kom (2016) 0498 - Ingen titel

PSURs submitted to NCAs

6 000

5 000

4 000

3 000

2 000

1 000

2012 Jul-Dec

2013

2014

There were 62, 151 and 116 PSUR worksharing procedures for purely nationally authorised

medicines during the same periods (where one country acted as ‘reference Member State’,

carrying out the review on behalf of other countries). Since the last quarter of 2014 all nationally

authorised medicines containing substances listed in the EURD list will have a PSUSA reviewed

by the PRAC, which should increase the consistency of the review and allow Member States

access to a shared pool of expertise.

An example of the way in which the PSUR can lead to further action to ensure safety, as well as

of the checks and balances built into the system, is the strontium ranelate containing medicines

Protelos and Osseor:

Case study: Protelos/Osseor and risk of cardiovascular (heart and circulatory) events

What is Protelos/Osseor

Protelos (strontium ranelate) is a medicine approved for the treatment of osteoporosis (a bone

disorder associated with weakness of the bones and an increased risk of fractures). This medicine

(also marketed as Osseor) was approved in the EU in 2004 for use in preventing fractures in

women who have been through the menopause, and extended for use in men in 2012. In March

2012, the product information of the medicine was amended to warn against use in patients who

were immobile or at risk of blood clots, following an EU level review of the risks of blood clots

in the veins (venous thromboembolism (VTE)) and severe allergic skin reactions

What were the PSUR findings?

PSURs for strontium ranelate are submitted on a three-year cycle. In April 2013, the PRAC

completed a routine PSUR of the medicine, which included key data from studies in around 7 500

post-menopausal women, which showed an increased risk of heart attack (myocardial infarction)

and VTE in women taking the medicine who had uncontrolled high blood pressure or a past

See Community register:

http://ec.europa.eu/health/documents/community-register/html/h288.htm

and the EMA

assessment report:

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-

_Variation/human/000560/WC500131789.pdf.

kom (2016) 0498 - Ingen titel

history of circulatory or heart problems. As a result, the PRAC recommended further restriction

of the product’s use as an interim risk-minimisation measure, and considered further in-depth

analysis of the data was needed.

What happened next?

In May 2013, the European Commission requested a further in-depth review by the PRAC (a so-

called Article 20 referral). This was carried out in a matter of months, and initially led (in January

2014) to a recommendation that the medicine’s marketing authorisation should be suspended.

The PRAC recommendations were forwarded to the CHMP. While in overall agreement with the

PRAC analysis of the risks, the CHMP considered that the medicine might still have a place for

patients with no alternative treatment, provided they were carefully monitored for the

development of cardiovascular problems. After further discussion, it therefore agreed to restrict

the use of the medicine to patients who could not be treated with other medicines approved for

osteoporosis and that treatment should be stopped if patients developed heart or circulatory

problems. As previously recommended, use should be avoided in patients with a history of such

problems.

Conclusions

The case16 illustrates the value of routine reassessment of benefits and risks in delivering timely

and risk-proportionate regulation. The two committees working together, with complementary

knowledge and expertise, allowed the best balance to be achieved between the acknowledged

risks of the medicine on the one hand and the unmet medical need of those with few treatment

alternatives on the other.

Additional monitoring

In 2013, the EU introduced a new system to label medicines that are being monitored particularly

closely by regulatory authorities

. These medicines are described as being under 'additional

monitoring' and are monitored more intensively than other medicines. This is generally because

there is less information available, for example because a medicine contains a new active

substance, is a biological product, or it has been approved in circumstances where there are

limited data on its long-term use. Additional monitoring does not mean that the medicines are

unsafe.

Medicines under additional monitoring have a black inverted triangle displayed in their package

leaflet and in the information for healthcare professionals called the summary of product

characteristics, together with a short explanation that the symbol means the product is subject to

additional monitoring and particularly encouraging users to report suspected side effects. There

was a consultation of the Member States and other stakeholders, especially patients and

healthcare professionals, on the choice of symbol and its implementation.

The black triangle is now being used in all EU Member States to identify medicines under

additional monitoring. It started appearing in the package leaflets of the medicines concerned

from the autumn of 2013, and was accompanied by a communications campaign to the public,

European Medicines Agency. Protelos/Osseor to remain available but with further restrictions (published

18/09/2014). Available at:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Protelos_and_Osseor/human_referr

al_prac_000025.jsp&mid=WC0b01ac05805c516f.

Defined by Article 23 of Regulation (EC) No 726/200 and Article 11 of Directive 2001/83/EC; the implementing

regulation for the black symbol is Commission Implementing Regulation (EU) No 198/2013 of 7 March 2013 on the

selection of a symbol for the purpose of identifying medicinal products for human use that are subject to additional

monitoring, OJ L 65, 8.3.2013, p. 17.

kom (2016) 0498 - Ingen titel

developed by Member States, the EMA and the European Commission with the aid of relevant

stakeholders

. In addition, a European list of medicines under additional monitoring is published

and is updated monthly to include new medicines and any changes in monitoring status of those

on the list

. At the end of 2014 the list included 193 centrally authorised and 8 nationally

authorised medicines. The annexes related to medicines that had certain conditions imposed, for

example as an outcome of referrals, included a further 1 269 nationally authorised medicines.

Referrals

see also

Annex 5

A pharmacovigilance

referral

is a procedure used to resolve issues such as concerns

over the safety or the benefit-risk balance of a medicine or a class of medicines. The

matter is ‘referred’ to the European Medicines Agency, so that it can make a

scientific assessment leading to a recommendation for a harmonised position across

the European Union.

Pharmacovigilance referrals follow a defined procedure. The PRAC appoints

members as rapporteurs and co-rapporteurs, and their expert teams in the Member

States perform an initial assessment of the data on the PRAC’s behalf to help it

reach its recommendations. An opinion is then provided either by the CHMP (for

referrals including centrally authorised medicines) or CMDh (for nationally

authorised medicines). This is passed to the European Commission for a final,

legally binding decision (except for consensus decisions of CMDh, which can be

implemented directly at national level).

Pharmacovigilance referrals can be governed by several articles of the legislation.

Procedures triggered when it is considered that urgent action for nationally

authorised medicine(s) is necessary because of a safety issue are covered by

Article

107(i)

of Directive 2001/83/EC. Concerns relating to the safety or benefit-risk of a

medicine or a class of medicines that include nationally authorised products are

assessed by procedures triggered under

Article 31

of Directive 2001/83/EC. Safety

or benefit-risk issues with medicines that have been authorised via the centralised

procedure only are covered by

Article 20

of Regulation (EC) No 726/2004.

A total of 31 safety referrals were dealt with by the PRAC over the reporting period. Nine of

these referrals involved centrally authorised medicines, the remainder dealt solely with nationally

authorised products.

European Medicines Agency. Medicines under additional monitoring. Available at:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000365.jsp

&mid=WC0b01ac058067bfff.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000366.jsp

kom (2016) 0498 - Ingen titel

The outcomes of these referrals included variations of marketing authorisation in 24 cases,

suspensions of marketing authorisation in 6 cases (reversible if the marketing authorisation holder

can provide new evidence to justify the lifting of the suspension), and permanent revocations of

marketing authorisation in 4 cases. (When a referral concerns a group of medicines, combined

outcomes, such as variations of certain indications within the marketing authorisations and

revocation of others, are possible.)

The revised legislation has improved the efficiency of the referral procedure, providing a more

flexible and more transparent mechanism for reviewing safety and resulting in more effective and

co-ordinated action to protect public health across the EU when needed.

The increased flexibility available with the new legislative tools, the greater transparency and the

involvement of patient and healthcare professional representatives have had important impacts on

safety referrals during this period, as illustrated by the below case study.

Case study: Combined hormonal contraceptives (CHCs), Article 31 referral on risk of

thromboembolism

What was the reason for the referral?

Current combined hormonal contraceptives (CHCs) contain two types of hormone, a low dose of

an oestrogen together with one of a number of different progestogens. They have long been

known to be associated with a rare but serious increased risk of clots forming within blood

vessels (thromboembolism) and the type of progestogen chosen can influence this risk, as can

risk factors affecting the woman taking the medicine.

Although reviews of this risk have previously taken place at both national and European level,

with consequent changes to their product information, in February 2013 the French medicines

regulator, ANSM, asked for a referral under Article 31 to further review the benefit-risk of CHCs,

focusing particularly on information about the risk of thromboembolism and advice on reducing

it. This was because of further data about the risk of thromboembolism and consequent

complications such as pulmonary embolism, in CHCs containing newer progestogens rather than

the older progestogens levonorgestrel or norethisterone.

What evidence was reviewed?

The PRAC reviewed the available data from clinical trials, pharmacoepidemiological studies,

published literature and spontaneous reports of suspected adverse drug reactions as well as the

kom (2016) 0498 - Ingen titel

views of an ad-hoc expert meeting. This represented a large amount of high quality evidence and

provided information from many millions of woman-years of use.

What were the recommendations of the scientific review?

In October 2013 the PRAC confirmed that CHCs provide highly effective contraception and their

benefits continue to outweigh their risks as the risk of thromboembolism in the veins (VTE) is

small. It confirmed that there were differences in this small risk depending on the progestogen

chosen, with the lowest risk attached to the progestogens levonorgestrel, norethisterone or

norgestimate. A table of relative risks was adopted by the PRAC following input from patient and

healthcare professional representatives.

Risk of developing a blood clot (VTE) in a year

Women not using a combined hormonal

pill/patch/ring and are not pregnant

Women using a CHC containing

levonorgestrel, norethisterone or norgestimate

Women using a CHC containing etonogestrel

or norelgestromin

Women using a CHC containing

drospirenone, gestodene or desogestrel

Women using a CHC containing

chlormadinone, dienogest or nomegestrol

About 2 out of 10 000 women

About 5 to 7 out of 10 000 women

About 6 to 12 out of 10 000 women

About 9 to 12 out of 10 000 women

Not known at time of review so studies

were expected or recommended to allow

estimation of the risk

The PRAC recommended modifying the product information of CHCs to give up-to-date

information to women and prescribers on the risks and how to minimise them, and

communicating the outcome of the review through educational materials including a letter to

healthcare professionals.

What was the outcome?

The PRAC’s recommendations were supported by the CHMP, which gave a positive opinion on

the recommendations in November 2013, and the European Commission adopted a legally

binding decision in January 2014 modifying the product information of all CHCs throughout the

Conclusions

Previous experience has shown that concerns about side effects of CHCs can, if mishandled, lead

to undesirable consequences including increases in the rate of unintended pregnancy (which itself

can increase the risk of VTE) and abortion. The 2013 referral was a good example of the way that

the tools and expertise now available to the EU network allowed for a rapid, collaborative review

of the available evidence, with unprecedented levels of transparency and communication co-

ordinated across the network, without triggering excessive public concern. The involvement of

European Medicines Agency. Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks

(published 31/01/2014). Available at:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Combined_hormonal_contraceptive

s/human_referral_prac_000016.jsp&mid=WC0b01ac05805c516f.

kom (2016) 0498 - Ingen titel

patient and healthcare professional representatives was key to ensuring that the risks and benefits

of the medicines were communicated clearly and appropriately. The ultimate outcome is that

women and prescribers have the best available evidence to support making an informed decision

about the choice of contraceptive.

Another case-study of a referral, illustrating the important input of those affected by adverse

effects, is included under

Cooperation and Coordination with Stakeholders,

below.

Issues that do not lead to referral

Some additional concerns at a national level which could potentially have led to a referral under

Article 107(i) were also discussed by the CMDh to decide on whether an EU level assessment

was required but did not ultimately trigger a referral. Such discussions were held on two

occasions in 2013 and six in 2014.

Post-authorisation studies

see also

Annex 6

post-authorisation safety study

(PASS) is a study that is carried out after a

medicine has been authorised to obtain further information on its safety, or to

measure the effectiveness of risk-management measures. Under EU legislation,

regulators may proactively impose a requirement for a PASS on a marketing

authorisation holder or may require one as part of the risk management plan because

of an identified safety concern before or after marketing.

The protocol for imposed non-interventional PASSs (i.e. their proposed study

design) and their final outcomes are assessed by the PRAC. (A

non-interventional

study

is one in which the medicine is prescribed in accordance with the approved

indication, and patients who receive it do so in accordance with normal medical

practice, with no special tests or monitoring.) All studies required by regulators are

included in the risk management plan.

In addition, companies may

voluntarily

carry out a PASS to identify or characterise

a safety concern, confirm the safety profile of a medicine, or measure the

effectiveness of risk minimisation measures.

The protocols and abstracts of the final study reports of PASSs are published in the

EU post-authorisation study (PAS) register on the European Network of Centres in

Pharmacoepidemiology and Pharmacovigilance (ENCePP) website.

Understanding the benefits as well as the risks of a medicine is important in

authorising its use. Sometimes, aspects of its efficacy may only be able to be

resolved after it has been marketed. In addition, changes in the understanding of

diseases or their study and treatment may mean that previous efficacy evaluations

need to be revised. In such instances

post-authorisation efficacy studies

(PAES)

may be required by regulators to complement available efficacy data.

The use of PASSs and PAESs represents a commitment from both regulators and marketing

authorisation holders to address gaps in the evidence base in a more proactive and planned way.

kom (2016) 0498 - Ingen titel

Post-authorisation safety studies

During the reporting period, the PRAC reviewed protocols for 38 imposed non-interventional

PASSs in order to approve them. In two cases the PRAC requested proposals for alternative study

designs. The review of PASS protocols and their results by the PRAC is increasing, so that by

2014 around 140 (nearly 10%) of the items on the Committee agenda related to PASS protocols

(some of these represented repeated consideration of the same protocol) and protocol results had

been discussed on some 50 occasions. Member States have also evaluated an additional 17 PASS

protocols for nationally authorised medicines.

No. of imposed non

interventional PASS protocols

for CAPs reviewed at PRAC

Jul-Dec 2012

2013

2014

Post-authorisation efficacy studies

Post-authorisation efficacy studies may be required by regulators in order to address some

efficacy aspects and complement the available data. Because both benefits and risks have to be

regularly assessed in order to be sure that the balance between them remains positive, post-

authorisation studies of efficacy can also have relevance in the context of pharmacovigilance

activities. A Commission Delegated Regulation (EU) No 357/2014

dealing with PAES was

adopted in February 2014, towards the end of the three-year period covered by this report, and

since this came into operation and up to July 2015, 14 PAES had been imposed by CHMP

(although many of these post-date the data-lock point). One additional PAES was required by a

Member State for a nationally authorised medicine.

Inspections

see also

Annex 7

Rigorous programmes of inspection underpin the pharmacovigilance system, as they do also for

the quality and manufacture of medicines. The ongoing work undertaken by inspectors helps to

ensure that EU citizens receive the safe, high-quality medicines they deserve.

The total number of inspections undertaken was 207 in 2012 (for the whole year), 195 in 2013

and 167 in 2014. The proportion of these related to centrally authorised medicines increased in

Commission Delegated Regulation (EU) No 357/2014 of 3 February 2014 supplementing Directive 2001/83/EC of

the European Parliament and the Council as regards situations in which post-authorisation efficacy studies may be

required, OJ L 107, 10.4.2014, p.1.

kom (2016) 0498 - Ingen titel

the same periods, being 26, 37 and 48 respectively. There were 9 inspections at the request of the

CHMP during 2012 (7 taking place in July-December), 6 in 2013 and 13 (of which 3 were

inspections of investigator sites related to conduct of a PASS) in 2014.

In 5 cases, penalties were imposed on marketing authorisation holders (MAHs) for failure to

comply with obligations.

Master files/logbook

The pharmacovigilance system in place for each medicine that receives a marketing authorisation

must be described by a pharmacovigilance system

master file,

held by the company, which

includes a description of the persons, places, and procedures put in place by them to monitor the

safety of the medicine. Companies must keep this file up to date and available for inspection, and

a logbook detailing the history of any changes to the file must also be maintained.

It is routine practice for a copy of the master file and logbook to be requested during all safety

inspections by the regulatory authorities.

Medication errors

see also

Annex 8

medication error

can be defined as an unintended failure in the drug treatment

process that leads to, or has the potential to lead to, harm to the patient. This can

include a patient taking or being given the wrong medicine, using the wrong dose or

route of administration, or a medicine being given to the wrong patient. Medication

errors do not necessarily lead to harm, however the cost to patients and healthcare

systems can be high, and many medication errors are preventable.

kom (2016) 0498 - Ingen titel

In 2012 there were around 4 500 side effect reports received by EudraVigilance associated with

medication errors, increasing to some 5 700 in 2013 and over 7 000 in 2014. It is likely that at

least some of the apparent increase may be due to increased awareness and better reporting, in

itself a positive outcome from the new legislation.

In the EU, national competent authorities and the EMA play a key role in identifying and

reducing the risk of medication errors before and after the authorisation of a medicine. Direct

patient reporting of side effects, including those caused by medication errors, as brought in by the

revised pharmacovigilance legislation assists regulatory authorities in implementing risk

minimisation measures at an early stage and avoiding further harm due to these errors.

Communication about medication errors is an important tool in reducing the risk. The Member

States play a major role in such communication, along with other channels such as direct

healthcare professional communications (DHPCs), educational material and communications

from national patient safety organisations. Going forward, the EMA has prepared proposals to

streamline its current ‘safety communications’ to consistently capture key information related to

medication errors which are assessed

Individual Case Safety Reporting to

by its scientific committees as a

EudraVigilance - medication errors

complement to information issued at

(EEA)

a national level and a dedicated area

8 000

on the its website will provide links

to such communications

7 000

6 000

5 000

4 000

3 000

2 000

1 000

2011

2012

CAPs

NAPs

2013

2014

A workshop took place in 2013

involving Member States and the

EMA with stakeholders from all areas

of healthcare to develop and share

best practices for the prevention of

medication errors. It helped develop a

subsequent

action

plan

for

implementation during 2014 to 2015

on how the EU system could

complement and facilitate (within

existing frameworks) the extensive

local and national programmes

carried out in the Member States

The clearer focus on medication errors as part of the pharmacovigilance process and the

availability of new tools in the legislation that can be used to address them is expected to help

reduce the harm that results from them.

OMMUNICATIONS AND TRANSPARENCY

In order for the EU regulatory network to function, good communication between its constituent

members, and between the network and the wider public it ultimately serves, is vital. The system

operates with a high level of transparency, as foreseen and guaranteed by legislation, and

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000398.jsp

&mid=WC0b01ac058098f1c0

See European Medicines Agency. Medication errors:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000570.jsp&mid=WC

0b01ac0580659655.

kom (2016) 0498 - Ingen titel

communicates synchronously to the public about safety concerns of medicines at different stages

of the regulatory process.

As mentioned above under

Side-effect reporting,

Member States engage extensively with the

media and relevant stakeholders to communicate relevant safety messages and promote public

understanding of issues of medicines safety. A survey conducted though the SCOPE project

showed that all 25 Member States who responded also provide safety-related information on a

website, which may include information for healthcare professionals, industry and patients on

different ways to report side effects. The survey found that 11 Member States have national/local

guidelines stating what information should be presented on the website. At the time of the survey,

some Member States were in the process of introducing changes to their web-pages including

tailoring the information to audience type.

The increased work being done to assure the safety of medicines under the revised EU

pharmacovigilance system has been complemented with greater public availability of information

on the interim steps and outcomes of that work. The

agendas

and

minutes

of the monthly formal

PRAC meetings are made available on the EMA website, and

highlights

of the outcomes are

published the next working day after the conclusion of the meeting.

The system produces public safety communications on relevant issues, including announcements

of the

start of referrals,

communication of the

recommendations issued by the PRAC,

and

detailed

public health communication

of the final outcome (including elements tailored

specifically to patients and healthcare professionals, which are produced with input from

representatives of the relevant stakeholder groups). There were 14 such communications issued in

the second half of 2012, 78 in 2013 and 57 in 2014.

In addition, a pilot project to produce

public summaries of the RMP

has been carried out. A

summary was prepared for each new medicine approved centrally in 2014, resulting in a total of

54 such summaries being published. A survey of stakeholder responses to this pilot will inform

the content and nature of future RMP summary publication.

The EMA helps co-ordinate communications within the EU network, providing an

Early

Notification System

(ENS) to the national competent authorities, the European Commission and

other network partners, which provides early warning of safety issues on the PRAC, the CMDh

or the CHMP agendas.

Lines-to-take

for press and communication officers in the Member States

to reply to enquiries from the media or other stakeholders are co-ordinated by the EMA with

input from internal and scientific experts from national medicines regulators. Such lines-to-take

were distributed within the network on 46 occasions from June-December 2012, 75 in 2013, and

47 in 2014.

In addition to the detailed communication on referrals already mentioned, public access to

aggregated data from reports of suspected side effects contained in EudraVigilance has been

ensured through the

European database of suspected adverse drug reaction reports

which

was launched in 2012 at the start of the period covered by this report. Initially providing access to

suspected side effects for centrally authorised medicines, and subsequently extended in October

2014 to provide information on common active substances included in nationally authorised

medicines. It now covers over 500 active substances for centrally authorised products and more

than 1 500 for nationally authorised medicines. More detailed information can be made available

to selected stakeholders on application, in accordance with the EudraVigilance access policy and

data protection laws.

http://www.scopejointaction.eu/

http://www.adrreports.eu

kom (2016) 0498 - Ingen titel

Details of recommendations made by the PRAC about signals are published monthly. When there

is a recommendation for a change to product information the changes are translated into all

official EU languages and published by the EMA as a service the Member States and to industry.

The outcomes of

imposed PASS studies

are available in the register on the ENCePP website

Full

RMPs

are not published (although they can be made available via EMA’s access to

documents policy), but as already mentioned summaries in public-friendly language are being

published for new medicines approved since 2014.

Work has also taken place to allow for greater transparency on the outcomes of single-assessment

PSURs (PSURs for a group of medicines all containing the same active substance or combination

are considered together). The

outcomes of PSURs

for centrally authorised medicines which

recommend changes to the marketing authorisation are published on the EMA website as part of

each medicine’s European Public Assessment Report (EPAR). The outcome for nationally

authorised medicinal products included in 'mixed' procedures where centrally authorised products

were also involved can be found on the Community register

. As of mid-2015, conclusions of

PSUR single assessments related to only nationally authorised medicines are also being

published

Transparency as an underlying principle of communications

The high degree of transparency about pharmacovigilance issues, in which not only outcomes but

processes are communicated, carries some risks of causing alarm amongst medicines users and

wider civil society. It is acknowledged that this could have unintended consequences for public

health (e.g. patients discontinuing beneficial medicines). Interaction with stakeholders is

therefore crucial in ensuring that risks are communicated clearly, accurately and proportionately

and in the context of the potential benefit.

In the long-run trust in the regulatory system requires this transparency, which forms part of a

wider transparency agenda

in which European legislators and regulators are playing a leading

role; ever more of the clinical evidence on which decisions about medicines are made is

becoming publicly available. The greater transparency and communication brought about by the

new legislation in terms of pharmacovigilance fosters an environment in which transparency is

seen as a norm. This encourages openness and communication about other regulatory processes.

YSTEMS AND SERVICES IMPROVEMENT

The role of the EMA includes the provision of some of the systems and services needed for the

pharmacovigilance network to function. The new legislation has required the development of

some new systems and services and enhancement or simplification of others. Member States and

key stakeholders including the pharmaceutical industry have had an important input to the design

and development of these systems.

The revised legislation foresees that pharmacovigilance activities conducted at EU level for

human medicinal products should be financed by

fees

paid by marketing authorisation holders

http://www.encepp.eu/encepp_studies/indexRegister.shtml

http://ec.europa.eu/health/documents/community-register/html/index_en.htm

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000620.jsp&mid=WC0b01

ac0580902b8d

Regulation (EU) No 658/2014 of the European Parliament and of the Council of 15 May 2014 on fees payable to

the European Medicines Agency for the conduct of pharmacovigilance activities in respect of medicinal products for

human use, OJ 189, 27.6.2014, p.112.

kom (2016) 0498 - Ingen titel

These additional resources will be used to remunerate the national competent authorities of the

Member States for the pharmacovigilance assessments they carry out as rapporteurs for the

PRAC and to contribute to the pharmacovigilance-related costs of the EMA, including the system

improvements described in this section of the report. The Article 57 database referred to below

supports routine pharmacovigilance business processes, as well as the collection of

pharmacovigilance fees.

Article 57 database

database

of all authorised medicines (both centrally and nationally authorised) in

the EU has been developed over the reporting period, as originally envisaged in

Article 57

of Regulation (EC) No 726/2004 and developed in the updated

pharmacovigilance legislation. Maintaining this information in a single location is

intended to reduce duplication of effort and costs, and improve the efficiency of

database and systems communication within the network, with international

partners, and with the industry. It will allow identification of products and

substances in reports of suspected side effects, in referral procedures and PSURs,

and is used to support collection of pharmacovigilance fees from the industry.

It is envisaged that this database will eventually support the provision of information

to patients and the public via a medicines web-portal.

The development of the Article 57 database and collecting and maintaining the medicinal product

entries received from the marketing authorisation holders, has been a considerable undertaking,

requiring close co-operation between the EMA and the industry. The database represents

information on over 580 000 medicines from nearly 4 300 marketing authorisation holders. The

information was updated by submissions from the companies during 2014, and the database

started to enter routine use and maintenance in 2015.

EudraVigilance enhancements

The legislation requires enhancement of EudraVigilance to support simplified reporting, better

search, analysis and tracking functions, and improved data quality. The database needs to support

the Member States in their requirement to monitor reports of suspected side effects and to support

industry in monitoring the safety of its products. The enhancements will include compliance with

various international data standards, which will facilitate data exchange. Significant progress on

enhancing the EudraVigilance database has been made during the reporting period including the

launch of the ADR website, the support to signal detection activities through production and

distribution to the Member States of data outputs from the system, and in the planning and

building of the enhanced system with its new functionalities and new data structure. At the time

of reporting the development of the system is on track to undergo in early 2018 the audit foreseen

in the legislation.

Literature monitoring service

The EMA is required to monitor selected medical literature for reports of suspected side effects to

certain active substances, and enter them into the EudraVigilance database as ICSRs

. This

Further information on the EudraVigilance database is available in the annual report foreseen under Article 24(2)

of Regulation (EC) No 726/2004

(http://www.ema.europa.eu/docs/en_GB/document_library/Report/2016/03/WC500203705.pdf)

Article 27 of Regulation (EC) No 726/2004.

kom (2016) 0498 - Ingen titel

should enhance the quality of the safety information available, and it is hoped will reduce the

administrative burden on the industry for reporting for the relevant substances. Preparation of the

EudraVigilance system to perform this service was completed in 2014 and the service was

launched in June 2015.

PSUR repository

The legislation creates a legal requirement to set up a repository for all PSURs

and their

assessment reports. This will considerably simplify the submission process for the pharmaceutical

industry and provide ready access by regulators via a user interface that will allow search and

retrieval of documents.

The repository has been developed during the reporting period, with system feedback supplied by

Member State and industry users, and the repository was made available and audited for

functionality during 2015. Use of the repository for the submission of PSURs will become

compulsory in mid-2016.

OOPERATION AND COORDINATION WITH REGULATORS

Within the EU network

The EU regulatory network requires close co-operation and co-ordination between over 30

national competent authorities, the EMA and the European Commission. The updated legislation

has aimed to facilitate this by strengthening the network, reducing duplication, and clarifying

roles and responsibilities.

The PRAC is an important pillar of this improved system, with its members working at the

European level but supplying knowledge and perspectives developed within their national

agencies.

Improved and co-ordinated communication, including the Early Notification System and the use

of lines-to-take, has helped to ensure that the system speaks coherently to external stakeholders,

so patients and the public receive consistent messages about the safety of their medicines across

the EU, and that Member States are made aware of developing issues in one country that may

lead to media interest in another. The development of improved systems and services over the

reporting period, in which Member State input has been crucial, should allow further

improvement.

International regulators and ICH

The EU pharmacovigilance system exists in the context of global safety monitoring and as part of

a tradition of long-standing cooperation between regulators and harmonisation of guidelines and

practices. The EMA acts as a central point of contact with other major regulators, in particular the

US Food and Drug Administration (FDA), Health Canada and the Japanese regulatory

authorities. Confidentiality arrangements between regulators permit sharing of critical data and

expertise related to safety issues and product assessments, and assist timely and co-ordinated

communication about relevant issues (for example, by giving early warning of safety-related

communications that may generate public concern or media enquiries). Based on the successful

product-related collaboration, the system has also concluded on strengthened strategic

collaboration with the FDA, via the so-called international pharmacovigilance cluster

. The EU

Article 25a of Regulation (EC) No 726/2004.

European Medicines Agency/FDA/ Guiding principles for the international pharmacovigilance cluster,

22 May 2015. Available at:

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/12/WC500179390.pdf.

kom (2016) 0498 - Ingen titel

network’s best practice have been shared with external regulators via training courses and

workshops.

The members of the EU regulatory network play a key role in developing harmonised guidelines

for human medicines regulators through the Association of the International Council for

Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH

brings together the regulatory authorities of Europe, Japan, the United States, Canada and

Switzerland, and experts from the pharmaceutical industry, with the aim of agreeing common

approaches and requirements where possible for the authorisation of medicines. The membership

in the ICH Association is expected to increase further.

An important outcome during the reporting period was the adoption by ICH of a new guideline

on the format and content of periodic benefit-risk evaluation reports

, based on the approach for

PSURs brought in by the new EU pharmacovigilance legislation.

OOPERATION AND COORDINATION WITH STAKEHOLDERS

Patients and healthcare professionals

Patients and healthcare professionals are key stakeholders in the revised European

pharmacovigilance system, since they are the people actually prescribing, dispensing and using

medicines. The PRAC membership therefore includes representatives of these groups, who have

input to all the activities of the Committee, and supply relevant perspectives to all aspects of its

work. Broader consultations with patient and healthcare professional organisations may form part

of referrals and a patient representative is included in scientific advisory groups (SAGs), expert

groups convened to supply specialist input. Patient and healthcare professional representatives

also review relevant safety communications. Work has also been undertaken in preparing for

future public hearings in the context of referral procedures.

The importance of involving these critical stakeholders is illustrated by the review of valproate

and related substances in pregnant women, an Article 31 referral which began in October 2013.

Case study: Valproate and related substances, Article 31 referral

What

was the reason for the referral?

Valproate and related medicines are nationally authorised medicines that have been used for

many years to treat epilepsy and bipolar disorder, and in some Member States are also authorised

to prevent migraine. It has been known for many years that use in pregnant women increases the

risk of certain birth defects in children, and evidence has also built up that they may result in a

delay in the child’s development. In October 2013, the UK requested a review of these medicines

following the publication of new studies suggesting that in some children effects on development,

which could include autism, might be long-lasting.

What evidence was reviewed?

The PRAC reviewed available studies and reports providing the most recent evidence on harms,

including both congenital malformations and long-lasting developmental disorders, and

importantly, consulted representatives of patients and families who had been affected as well as a

group of experts and specialists in fields such as neurology, child development and obstetrics.

Patient representatives were thus actively involved in the process and had significant input into

ICH guideline E2C (R2) on periodic benefit-risk evaluation report.

kom (2016) 0498 - Ingen titel

the development of risk minimisation measures.

What were the recommendations of the scientific review?

The PRAC recommended a strengthening of warnings in the product information to ensure that

healthcare professionals and patients were aware of the risks and that patients were prescribed

valproate only when clearly necessary. Educational materials were recommended so that women

and healthcare professionals were better informed about the risks of valproate exposure in the

womb and of the need for effective contraception while using it, and it was advised that treatment

should be regularly reviewed by doctors, including at puberty and when a woman wished to

become pregnant.

What was the outcome?

Since these medicines were all authorised nationally, the recommendations were sent to the

CMDh which endorsed them by consensus in November 2014, and they were implemented by the

Member States according to an agreed timetable.

Conclusions

The referral shows the way in which the regulatory system can incorporate the experiences and

concerns of patients and sufferers from adverse reactions into a rigorous and timely review

process, resulting in better information for users of the medicines and more appropriate use of a

valuable but potentially problematic treatment for these serious conditions.

The EMA interactions with patient and healthcare professional representatives are managed in

line with an agreed framework for interaction designed to minimise conflicts of interest.

At the Member State level many interactions also take place between the various national

medicines regulators and national patient and healthcare professional organisations. A survey of

national competent authorities carried out in January 2015 by the Working Group of

Communication Professionals (representing the Member States) and the EMA found that 85% of

respondents had formal or semi-formal interactions with patient groups and representatives. This

has been particularly true in the area of side effect reporting where some Member States work

directly with patient organisations to facilitate side effect reporting, and 13 of them work with

patients or patient representatives to user-test side effect reporting forms.

Following the establishment of the PRAC and the bedding in of the new legislation, improved

procedures for drafting and reviewing safety communications to healthcare professionals

(DHPCs) were also developed, to ensure that these were appropriately reviewed by members of

the relevant committees and their content was clear.

Academia

Academia plays a significant role in generating the evidence on which regulators rely to make

judgements about the benefits and risks of medicines. In pharmacovigilance, the EU network has

engaged actively with academia, most notably through the European Network of Centres for

Pharmacoepidemiology and Pharmacovigilance (ENCePP). Engagement has also occurred

through regulatory science projects, particularly the Innovative Medicines Initiative (IMI) funded

EU PROTECT

project on pharmacovigilance methods.

Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium.

kom (2016) 0498 - Ingen titel

The industry

The pharmaceutical industry is a key actor in pharmacovigilance. Individual marketing

authorisation holders have specific responsibilities under the legislation in terms of running a

system of pharmacovigilance, monitoring and reporting for their products. The EU network has

strengthened its communication and consultation with industry on draft guidance and through a

regular ‘Industry Platform’ where representatives of EU industry associations meet with

regulators.

The media

Press and communication departments of the national competent authorities and of the EMA

interact regularly with local and international media to encourage side-effect reporting and

disseminate important safety-related messages and outcomes of regulatory processes as described

under

Communications,

above.

The national regulators, with their close understanding of the healthcare and media environment

within their own countries, play a key role in ensuring safety-related messages are clearly

understood and disseminated in each Member State in appropriate ways. Timely provision of

lines-to-take and safety communications to the Member States is important in supporting this

work.

Press releases and communications strategies are developed for areas of particular public interest,

including referrals such as those related to hormonal contraceptives or the medicine Diane 35

(cyproterone and ethinyloestradiol, a hormonal combination approved for the treatment of women

with severe acne). The network works to ensure that strategic messages and important issues are

communicated appropriately to the media.

HARMACOVIGILANCE AND PUBLIC HEALTH

While medicines save lives and prevent suffering, the burden of adverse drug reactions is

considerable: some 5% of hospital admissions in the EU and around 197 000 deaths per year have

been thought to be due to adverse reactions to medicines

Experience to date suggests that the revised pharmacovigilance system now in place in the EU is

resulting in more timely and consistent outcomes to optimise the safe and effective use of

medicines. This is based on risk-proportionate scientific decisions made on the basis of the best

available evidence. Fast and robust detection of issues, decision-making and communication to

users of medicines allows those users to make informed decisions and reduces risks from the use

of the medicines, thus benefiting public health. Furthermore, efficiencies gained by working in a

network can make more efficient use of resources.

The existence of reliable systems for monitoring drug safety and pro-active planning of data

collection and ways to minimise those risks in the form of RMPs and post-authorisation studies is

important in supporting authorisation of new and innovative medicines.

Work is ongoing to develop better measurements for the impacts of pharmacovigilance including

health outcomes and the PRAC strategy on health impact measurement was published in 2016

It is expected that the strategy will support the collection of more data relevant to the health

impact of the EU pharmacovigilance system which can be relevant for subsequent reports.

Annex 2 of the Report on the impact assessment of strengthening and rationalising EU Pharmacovigilance,

Commission of the European Communities, Sept 2008.

European Medicines Agency, PRAC strategy on health impact measurement, EMA/790863/2015, 11 January

2016.

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ONTINUING AND FUTURE DEVELOPMENT OF THE NETWORK

Training

The national competent authorities of the Member States and the EMA offer programmes of

internal and external training on the infrastructure and procedures required for

pharmacovigilance. This has included training to familiarise regulators, industry and other

stakeholders with the details of the revised legislation, the guidelines on good pharmacovigilance

practices, and the updated processes for data submission and analysis. For example, in 2014

alone, 24 training sessions on EudraVigilance data submission, 11 training sessions on the

medicinal product dictionary used by EudraVigilance (xEVMPD) and two introductory sessions

to EudraVigilance took place, along with access to the xEVMPD e-learning platform by 250

users.

Measures have been put in place during the period covered by the report to improve training

within the network, in the form of a joint initiative between the EMA and the Member States to

develop an

EU Network Training Centre

(EU NTC). The initiative was agreed in 2014, and is

intended to ensure that the best scientific and regulatory practices are spread across the network,

through the provision of high quality and relevant training materials shared through the EU NTC

platform. In addition to ensuring harmonised standards and providing professional development

for regulatory staff, it should reduce duplication of effort and thus ensure that resources available

for training are used most effectively.

Process improvement

Based on the experience of the first years of operation of the new EU pharmacovigilance

legislation and in dialogue with stakeholders, the EU network is putting effort into increasing

both the efficiency and effectiveness of pharmacovigilance processes. This can be seen through

revised processes, revisions to guidelines on good pharmacovigilance practice and through the

development of systems and services such as medical literature monitoring and the PSUR

repository. Further processes improvement will be a focus for the next period, based both on

experience and the results of regulatory sciences.

Building capacity and improving regulatory science

A number of projects have been initiated during the reporting period to improve the science and

practice of pharmacovigilance, and so enable future improvements in the system.

The Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint

Action will run from 2013 until 2016. It is an EU-funded ‘Joint Action’ with contributions from

the involved Member States, designed to understand how regulators in EU countries run their

national pharmacovigilance systems. Using this information, SCOPE will develop and deliver

guidance and training in key aspects of pharmacovigilance, along with tools and templates to

support best practice

. Survey data from the Member States obtained under the auspices of

SCOPE has been used in the preparation of this report.

Work to encourage the conduct of high quality, multi-centre, independent post-authorisation

studies is also ongoing within the context of the European Network of Centres in

Pharmacoepidemiology and Pharmacovigilance

. This is a partnership involving 147 centres

across Europe that brings together expertise and resources in pharmacoepidemiology and

pharmacovigilance. The EU register of these studies is available from its website. It also develops

methodological standards and governance principles for such studies.

Progress in the various work packages that constitute the project is reported on a dedicated website:

http://www.scopejointaction.eu/.

http://www.encepp.eu/index.shtml

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The

PROTECT

project (Pharmacoepidemiological Research on Outcomes of Therapeutics by a

European Consortium)

was a public-private partnership co-ordinated by the EMA which looked

at ways to strengthen safety surveillance and the monitoring of the benefit-risk of medicines in

Europe. This was to be achieved by developing new tools and methods for early detection and

assessment of adverse drug reactions, and finding improved ways to present data on benefits and

risks. These methods were tested in real-life situations in order to provide all stakeholders with

accurate and useful information supporting risk management and continuous benefit-risk

assessment. The project finished in 2015 and assessment of outputs for implementation into

routine practice is now underway, with new tools already being implemented in guidance and

systems (e.g. EudraVigilance).

Other regulatory science projects initiated during this period include WebRADR

which aims to

investigate apps for side-effect reporting and the role of social media data in this area of

pharmacovigilance and ADVANCE (Accelerated development of vaccine benefit-risk

collaboration in Europe)

which aims to establish a blueprint for a sustainable system for vaccine

benefit-risk monitoring in the EU. The EU invested 31.7 million euros into pharmacovigilance

research under the 7th Research Framework Programme, which ended in 2013.

ONCLUSIONS

The European pharmacovigilance network represents an example of successful co-operation at

the European level, to the benefit of EU citizens. The networked system allows all participants to

share in the best available expertise and evidence and co-ordinate the regulatory actions required,

producing more efficient and consistent outcomes for everybody. The regulatory tools made

available under the revised legislation, including risk management plans, post-authorisation

studies, signal detection and management at EU level, PSUR assessment and referrals, represent

an increasingly proactive approach to medicines safety, complemented by improvements in

regulatory action and communication when safety concerns are identified.

The system operates with high transparency, necessary to develop the trust of the society it

serves. Engagement of key stakeholders such as patients and healthcare professionals is

embedded in the system, and the perspectives they provide contribute significantly to the

decision-making process. For the future, deepening involvement is foreseen, including the

holding of public hearings for critical safety issues.

Work is proceeding on the infrastructure and procedures needed to support further development

of the system, and to simplify and streamline existing processes where possible so that the

regulatory burden is minimised for all stakeholders. Delivery of the medical literature monitoring

service, of the new EudraVigilance system and of the PSUR repository and full use of the Article

57 EU medicinal product database will increase efficiency and deliver simplification for

stakeholders. Work continues to complete the development and implementation of other systems

such as centralised ADR reporting through the EudraVigilance database. Ongoing research in the

field of regulatory science, will also support future improvements.

The work to implement the revised legislation and the increased level of transparency and

communication it brings has been challenging for all parties, but is now well established and has

opened new ways of communicating on medicines which are helping to set the tone for increased

communication and transparency in medicines regulation in general.

http://www.imi-protect.eu/

http://web-radr.eu/

http://www.advance-vaccines.eu/

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BBREVIATIONS

ADR

ADVANCE

adverse drug reaction (side effect)

Accelerated Development of VAccine beNefit-risk Collaboration in

Europe, a project to improve assessment of benefits and risks of

vaccines

Article 107(i) of Directive 2001/83/EC. It applies when, on the basis

of concerns resulting from the evaluation of data from

pharmacovigilance activities, a Member State or the European

Commission considers:



suspending or revoking a marketing authorisation (MA);



prohibiting the supply of a medicinal product;



refusing the renewal of a MA;



is informed by the marketing authorisation holder that, on the

basis of safety concerns, he has interrupted the placing on the

market of a medicinal product or has taken action to have a MA

withdrawn, or intends to take such action or has not applied for

the renewal of a MA.

Article 20 of Regulation (EC) 726/2004. It applies when a referral

procedure is initiated as a result of the evaluation of data relating to

pharmacovigilance of medicinal product(s) authorised via the

centralised procedure only.

Article 31 of Directive 2001/83/EC. It applies where the interests of

the Union are involved. When a referral procedure is initiated as a

result of the evaluation of data relating to pharmacovigilance of an

authorised medicinal product(s) the issue is referred to the

Pharmacovigilance Risk Assessment Committee.

Agence Nationale de Sécurité du Médicament et des Produits de

Santé, the French medicines regulator

centrally authorised product, a medicine for human use authorised by

the European Commission based on an evaluation by EMA

combined hormonal contraceptive

Committee for Medical Products for Human Use

Co-ordination Group for Mutual recognition and Decentralised

procedures – human

direct healthcare professional communication

European Commission

European Economic Area

European Medicines Agency

European Network of Centres in Pharmacoepidemiology and

Pharmacovigilance, a partnership involving 147 centres across

Europe

Art. 107i

Art. 20

Art. 31

ANSM

CAP

CHC

CHMP

CMDh

DHPC

EEA

EMA

ENCePP

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ENS

EPAR

EURD

early notification system

European public assessment report, a dossier of public information

relating to the approval of a medicine

European Union

List of European Union reference dates and frequency of submission

of periodic safety update reports (a list of active substances for which

PSURs must be submitted and the dates and frequencies at which this

should occur)

EudraVigilance, the database for collating suspected side-effect

reports that is maintained by EMA

granulocyte colony stimulating factor, a protein that stimulates white

blood cell production

good

pharmacovigilance

practice,

guidelines

pharmacovigilance activities should be carried out

healthcare professional

Association of the International Council for Harmonisation of

Technical Requirements for Pharmaceuticals for Human Use

individual case safety report, a standardised report of a suspected side

effect

Innovative Medicines Initiative, a public-private initiative aiming to

speed up the development of better and safer medicines for patients

information technology

lead Member State, a Member State who acts on behalf of the

network in assessing pharmacovigilance data for a particular active

substance

marketing authorisation holder, the company marketing a medicine

Medicines and Healthcare products Regulatory Agency, the UK

medicines regulator

nationally authorised product, a medicine evaluated and approved by

national regulators

National Competent Authority, a national medicines regulator

Network Training Centre

post-authorisation efficacy study

post-authorisation study

post-authorisation safety study

pharmacovigilance

Pharmacovigilance Risk Assessment Committee

Pharmacoepidemiological Research on Outcomes of Therapeutics by

a European Consortium, a public-private partnership to examine ways

G-CSF

GVP

HCP

ICH

ICSR

IMI

LMS

how

MAH

MHRA

NAP

NCA

NTC

PAES

PAS

PASS

PhV

PRAC

PROTECT

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to strengthen safety surveillance and the monitoring of the benefit-

risk of medicines in Europe

PSUR

PSUSA

RMP

SAG

SAR

SCOPE

periodic safety update report

periodic safety update – single assessment

risk management plan

Scientific Advisory Group

serious adverse reaction

Strengthening Collaboration for Operating Pharmacovigilance in

Europe, an EU-funded Joint Action project involving regulators from

many EU Member States plus Norway and Iceland

venous thromboembolism (a blood clot obstructing a vein)

a consortium developing a mobile app to report suspected adverse

drug reactions, and investigating the potential for publicly available

social media data for identifying drug safety issues

eXtended EudraVigilance Medicinal Product Dictionary

VTE

WebRADR

xEVMPD

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ANNEXES – technical data

The following annexes present the detailed numerical data which supports the text and figures in

the report. It has been collected by the Member States and the EMA, as detailed in the section

Sources of data

at the start of the report. The data should be read in conjunction with the

explanations and clarifications in the text of the report.

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NNEX

1a.

IDE EFFECT REPORTING

Number of individual case-safety reports (ICSRs) European Economic Area (EEA)

2011

January-

December

CAPs

Non

CAPs

Total

Patients

CAPs

Non

CAPs

Total

Patients and HCPs

CAPs

Non

CAPs

Total

Other sources*

CAPs

Non

CAPs

Total

Total no. of ICSRs

received (EEA)

CAPs

Non

CAPs

Total

No. ICSR reported

which have been

identified as subject

to medication error

(EEA)

CAPs

NAPs

Total

115 130

83 582

198 712

7 302

5 373

12 675

10 637

5 223

15 860

467

737

1 204

133 536

94 915

228 451

1 723

2 353

4 076

2012

January-

December

121 219

82 337

203 556

10 103

8 326

18 429

11 976

5 587

17 563

403

793

1 196

143 701

97 043

240 744

1 928

2 593

4 521

2013

January-

December

140 729

89 519

230 248

16 227

15 783

32 010

12 766

4 708

17 474

342

383

725

170 064

110 393

280 457

2 636

3 121

5 757

2014

January-

December

148 579

87 694

236 273

17 697

15 595

33 292

14 208

4 672

18 880

514

483

997

180 998

108 444

289 442

3 429

3 649

7 078

Postmarketing ADR

reporting (EEA)

Healthcare

professionals (HCP)

*Please note that ‘Other sources’ were combined with ‘Healthcare professionals’ for

charts on p. 10 - 11

kom (2016) 0498 - Ingen titel

1b.

Number of individual case-safety reports (ICSRs) non European Economic Area

2011

2012

2013

2014

ADR reporting

(non EEA)

Healthcare professionals

Patients

Other sources*

Patients and HCPs

258 879

46 502

11 555

100 980

324 089

143 257

11 714

134 532

332 291

212 777

11 935

156 794

363 704

210 179

17 310

174 361

*Please note that ‘Other sources’ were combined with ‘Healthcare professionals’ for

charts on p. 10 - 11

NNEX

2a.

IGNALS

Worksharing in signal management

kom (2016) 0498 - Ingen titel

2b.

Numbers of signals

2012

July-December

2013

January-

December

2014

January-

December

Signal reference data

CAPs

No. of signal

validated (total)

Non CAPs

Total

No. of signal

validated by

NCA

No. of signal

validated by

EMA

CAPs

Non CAPs

Total

CAPs

Non CAPs

Total

CAPs

No. of signal

confirmed (total)

Non CAPs

Total

CAPs

No. of EMA

signal confirmed

Non CAPs

Total

CAPs

No. of NCA

signal confirmed

Non CAPs

Total

CAPs

No. of signal not

confirmed (total)

Non CAPs

Total

No. of EMA

signal not

confirmed

No. of NCA

signal not

confirmed

CAPs

Non CAPs

Total

CAPs

Non CAPs

Total

kom (2016) 0498 - Ingen titel

2c.

Signal detection by lead Member State

Number of substances for signal

detection (lead Member State – LMS)

2012

2013

152

114

111

1 006

152

114

111

1 006

2014

168

115

102

1 000

Member

State

Germany (DE)

United Kingdom (UK)

Denmark (DK)

Sweden (SE)

Ireland (IE)

Netherlands (NL)

Finland (FI)

France (FR)

Hungary (HU)

Italy (IT)

Czech Republic (CZ)

Spain (ES)

Austria (AT)

Portugal (PT)

Romania (RO)

Belgium (BE)

Slovakia (SK)

Norway (NO)

Poland (PL)

Estonia (EE)

Latvia (LV)

Croatia (HR)

Bulgaria (BG)

Lithuania (LT)

Slovenia (SI)

Cyprus (CY)

Malta (MT)

TOTAL

kom (2016) 0498 - Ingen titel

NNEX

3a.

ISK MANAGEMENT PLANS

Number of Risk Management Plans

2012

June-December

3 553

2013

January-

December

637

7 356

2014

January-

December

597

8 992

No. of Risk

Management

Plans submitted

PRAC (CAPs)

National

competent

authorities

(NAPs)

For distribution of the RMPs for the NAPs authorised by Member State,

see

Annex 10.

3b.

Public Assessment reports as a measure of new approvals

2012

2013

2014

No. of Public

Assessment

Reports

published on

EMA's web-

portal for CAPs

New applications

Extension of

indications

RMP summaries

(from Apr 2014)

N/A

kom (2016) 0498 - Ingen titel

NNEX

4a.

OUTINE BENEFIT RISK MONITORING

(

PERIODIC SAFETY UPDATE REPORTS

)

Number of PSURs

2012

July-December

PSURs reviewed at

PRAC for CAPs only

PSURs reviewed at

PRAC for CAPS and

NAPS

Total number of

PSUR reviewed at

PRAC (CAP/NAP)

PSURs submitted to

an NCA for

assessment at national

level only (NAP)

2013

January-December

430

2014

January-December

426

436

471

5 093

3 726

3 310

For distribution of the PSURs for the NAPs authorised by individual Member State,

see

Annex

10.

4b.

PSUR worksharing

2012

July-December

No. of PSURs in

which one NCA acted

as lead Member State

2013

January-December

151

2014

January-December

116

4c.

Medicines under additional monitoring as of December 2014

List

Annexes

Total

201

No. annexes

NAPs

1 269

Total

CAPs

193

List + Annexes

Total

NAPs

1 277

Total -

All

1 470

CAPs

193

NAPs

kom (2016) 0498 - Ingen titel

NNEX

5a.

EFERRALS

Table of referral procedures, 2012-2014

Procedure name

INN (for overview)

Art.

Started

Triggered

Outcome

2012

Codeine

Diclofenac

SABA (Short Acting Beta

Agonists)

HES (Hydroxyethyl starch

solutions)

Almitrine

Diacerein

2013

Tredaptive

Trevaclyn

Pelzont

Tetrazepam

Cyproterone, ethinylestradiol

- DIANE 35 & other

medicines containing

cyproterone acetate 2mg and

ethinylestradiol 35

micrograms

Combined hormonal

contraceptives

nicotinic acid/laropiprant

tetrazepam

cyproterone/ethinylestradiol

107i

Jan-13

Feb-13

codeine

diclofenac

terbutaline, salbutamol, hexoprenaline,

ritodrine, fenoterol

hydroxyethyl starch

Oct-12

Nov-12

V,R

Nov-12

almitrine

diacerein

Nov-12

desogestrel, gestodene, norgestimate,

etonogestrel, drospirenone, dienogest,

chlormadinone, norgestimate,

nomegestrol acetate/estradiol,

norelgestromin/ethinylestradiol

flupirtine

domperidone

nicotinic acid, acipimox, xantinol

nicotinate

Feb-13

Flupirtine

Domperidone

Nicotinic acid and related

substances - acipimox,

xantinol nicotinate

Kogenate Bayer/Helixate

NexGen

107i

Mar-13

V,R

octocog alfa

Mar-13

kom (2016) 0498 - Ingen titel

Procedure name

INN (for overview)

Art.

Started

Triggered

Outcome

Renin-angiotensin system

(RAS)-acting agents

captopril, imidapril, zofenopril,

candesartan, delapril, telmisartan,

aliskiren, moexipril, enalapril,

valsartan, fosinopril, irbesartan,

perindopril, quinapril, ramipril,

eprosartan, olmesartan, trandolapril,

losartan, azilsartan, lisinopril, spirapril,

benazepril, cilazapril

strontium ranelate

glucose, lipids, amino-acids and

electrolytes

May-13

Protelos/Osseor

NUMETA G13%E,

NUMETA G16%E emulsion

for infusion and associated

names

Zolpidem-containing

medicinal products

Hydroxyethyl starch (HES) -

containing medicinal

products

Bromocriptine-containing

medicines

Valproate related substances

Iclusig

2014

Testosterone

Codeine for cough in

paediatric population

Ambroxol/Bromhexine

Methadone

Hydroxyzine

Corlentor and Procoralan

Ibuprofen and dexibuprofen

107i

May-13

Jun-13

V,S

zolpidem

Jul-13

hydroxyethyl starch

107i

Jul-13

bromocriptine

Sep-13

valproate

ponatinib

Oct-13

Dec-13

testosterone

codeine

Apr-14

V,R

ambroxol/bromhexine

methadone

hydroxyzine hydrochloride

ivabradine

ibuprofen and dexibuprofen

107i

Apr-14

May-14

Jun-14

V,S

Key to outcomes:

V=variation

of marketing authorisation;

S=suspension

of marketing

authorisation (can be lifted if new evidence is presented by marketing authorisation holder);

R=revocation

of marketing authorisation (permanent). A referral of a group of medicines may

result in differing outcomes for different medicines

kom (2016) 0498 - Ingen titel

5b.

Distribution of rapporteurships for referrals by Member State

NNEX

6a.

OST

AUTHORISATION STUDIES

Post-authorisation safety studies

2012

July-December

No. of imposed non

interventional PASS

protocols for CAPs

reviewed at PRAC

Nationally imposed

PASS

2013

January-December

2014

January-December

6b.

Post-authorisation efficacy studies

2014

CHMP imposed

National

kom (2016) 0498 - Ingen titel

NNEX

7a.

NSPECTIONS

Number of inspections

2012

No. of

pharmacovigilance

inspections performed

(CHMP mandated)

No. of

pharmacovigilance

inspections performed

(CAP programme)

No. of

pharmacovigilance

inspections performed

(EU total)

*7 from July-December 2012

**including 3 sites inspected for conduct of a PASS

7b.

Master file and logbook

2012

No. of occasions when

the MAH to submit a

copy of the PhV

system master file

2013

2014

2013

2014

13**

207

195

167

7c.

Imposed penalties on marketing authorisation holders

2012

July-December

2013

January-December

2014

January-December

No. penalties to

MAHs regarding

noncompliance with

their PhV obligations

*includes one local infringement notice issued

kom (2016) 0498 - Ingen titel

NNEX

8a.

EDICATION ERRORS

Individual case safety reports (ICSRs) related to medication errors

2012

July-December

No. ICSR

reported which

have been

identified as

subject to

medication error

(EEA)

Total no. of

ICSRs received

(EEA)

CAPs

NAPs

Total

2 547

CAPS

Non-CAPs

Total

76 833

51 669

128 502

5 757

170 064

110 393

280 457

7 078

180 998

108 444

289 442

NNEX

HARMACOVIGILANCE

CTIVITIES BY THE

PRAC

Items on PRAC Agenda

Workload

2012

(Jul-Dec )

Art.31 referrals

Art.107i referrals

Art.5(3) referrals

Signals

RMPs

PSURs

PASS Protocols

PASS Results

Renewals, Conditional Renewals and Annual

Reassessments

Pharmacovigilance Inspections

Other safety issues - CHMP

Other safety issues – Member State

Total items

127

637

438

104

1 534

118

597

470

137

1 521

2013

2014

1 173

1 374

2013

January-

December

2 636

3 121

2014

January-

December

3 429

3 649

159

kom (2016) 0498 - Ingen titel

NNEX

10.

HARMACOVIGILANCE

CTIVITIES BY

EMBER

TATES AT

ATIONAL

EVEL

n/a

366

232

426

138

217

3579

793

1187

1599

872

213

340

319

4 n/a

34 n/a

32 n/a

n/a

349

127

146

564

246

237

147

432

234

127

Totals

1327 1922

37 1085

421

66 1557 1539

250

492 1026

791

19901

243

398

237

286

248

203 n/a

3553

503

712

392

146

625

624

105

152

437

296

7356

581

812

456

210

646

667

106

265

386

495

8992

403

164

142

553

218 n/a

230 n/a

105 n/a

1094

414

412

268

328

84 n/a

148

432

156

165

111

5 n/a

0 n/a

1 n/a

822

341

195

286

11307

4752

3531

3024

Question\MS-->AT

DE-BfarmE-PEI

1. RMPs

213

139 2001

965

280

545

2012 Jul-Dec

436

146

2013

105

747

380

158

2014

818

439

149

382

2. PSURs

2012 Jul-Dec

2013

2014

3. PASS

2012 Jul-Dec

2013

2014

4. PAES

2014 May-Dec

5. Penalties

2012 Jul-Dec

2013

2014

1492

481

436

575

108

519

164

281

1204

218

346

640

2827

2074

491

262

157

250

21 n/a

109 n/a

120 n/a

0 n/a

n/a

0 n/a

n/a

0 n/a

Table shows entries for activity at purely national level for each EEA country participating in the pharmacovigilance network, except for

Luxembourg, Iceland and Liechtenstein for which no data were available.

Two sets of figures are shown for Germany, which has two NCAs (BfArm – the Federal Agency for Medicines and Health Products and

PEI – the Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines).

Where the data were not available this is indicated by n/a.

kom (2016) 0498 - Ingen titel