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04 April 2014 EMA/ 145085/ 2014 I nspect ions and Human Medicines Pharmacovigilance
2013 Annual Report on EudraVigilance for the European Parliam ent , the Council and the Com m ission Report ing per iod: 1 January to 31 December 2013
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© European Medicines Agency, 2014. Reproduct ion is author ised provided the source is acknowledged.
Table of Contents
1 . I nt rod uct ion ................................................... ......................................... 3
2 . Developm ent of new funct ionalit ies ................................................... ..... 3
3 . Data collect ion and data qualit y ................................................... ........... 4
4 . Data analysis ................................................... ........................................ 5
5 . Transparency, com m unicat ion and t ra in ing ............................................. 6
6 . Conclusion ................................................... ............................................ 7
Annex I - Sum m ary of EudraVigilance re lated act iv it ies .............................. 8
Annex I I – EudraVigilance data - processing netw ork and num ber of suspected adverse react ion repor ts processed by the EudraVigilance database ................................................... ................................................... 9
EudraVigilance data-processing network (EudraVigilance Gateway) ........ . . . . . . . . . . . . . . . . . . . . . . . .. . . 9
EudraVigilance database ........ . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
E- report ing status for MAHs and sponsors of clinical t r ials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . 12
E- report ing status for NCAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . 13
EudraVigilance database and support of signal m anagem ent process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Annex I I I - Tota l num ber of m edicinal product subm issions by MA Hs ....... 1 5
Annex I V - EudraVigilance data qualit y act iv it ies ...................................... 1 6
Annex V – Signal detect ion ................................................... ..................... 1 7
Overview of signals validated by the Agency priorit ised and assessed by the PRAC........... . 18
Annex VI - Signal m anagem ent in the EU .................................................. 2 2
Annex VI I - Requests for inform at ion and docum ents ............................... 2 3
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 2/ 28
1 . I n t roduct ion
The European Medicines Agency (EMA) works within the European Regulatory Network to support the
m onitoring of the safety of m edicines. The EMA's m ain responsibilit ies in this area include the
coordinat ion of the European pharm acovigilance system , the provision of inform at ion on the safe and
effect ive use of m edicines and operat ing and m aintaining EudraVigilance (EV) and the EudraVigilance
Data Analysis System (EVDAS) . Both EMA and m edicines regulatory authorit ies in Mem ber States are
required by legislat ion to cont inuously m onitor the adverse react ion data reported to EudraVigilance to
determ ine whether there are new r isks or known r isks which have changed and whether those r isks
have an im pact on the overall benefit - risk balance of a m edicine.
I n the context of the im plem entat ion of the new pharm acovigilance legislat ion 1, m ajor em phasis is
being been put on further st rengthening the role of EudraVigilance as regards sim plifying adverse
react ion report ing, collect ing adverse react ions reported by pat ients and consum ers (as well as those
from healthcare professionals) , detect ing new r isks, m onitoring known or potent ial r isks, r isk
assessm ent by the Pharm acovigilance Risk Assessm ent Com m it tee (PRAC) and increasing t ransparency
by providing stakeholders with adequate access to adverse react ion data and analysis (via EVDAS and
elect ronic React ion Monitor ing Reports, eRMRs) .
I n com pliance with the EU pharm acovigilance legislat ion 2, the EMA has prepared this annual report for
the European Parliam ent , the Council and the Com m ission to provide a sum m ary of the EudraVigilance
related act ivit ies that the EMA undertook in 2013 within the EU regulatory network and with
stakeholders.
2 . Developm ent of new funct ionalit ies
The revised pharm aceut ical legislat ion foresees further im provem ents in the funct ionalit y of EV. I n
accordance with Art icle 24 of Regulat ion (EC) 726/ 2004 3, the Agency, in collaborat ion with the Mem ber
States and the Com m ission, shall draw up the funct ional specificat ions for the EudraVigilance database
(hereafter referred to as “EudraVigilance funct ionalit ies to be audited” ) together with a t im efram e for
their im plem entat ion. The EudraVigilance funct ionalit ies to be audited focus on the key deliverables
which will benefit Mem ber States, pharm aceut ical indust ry and further st rengthen the protect ion of
public health. More specifically, they will deliver:
• Sim plificat ion of adverse react ion report ing
• High-qualit y and integrit y of pharm acovigilance inform at ion held in EudraVigilance
• Adaptat ion to technical and scient ific progress by im plem entat ion of the ISO standards for
individual case safety reports and ident ifying m edicines (subject to ISO t im elines)
• Full im plementat ion of the EudraVigilance Access Policy including access by m arket ing
authorisat ion holders to the extent necessary to fulfil their pharm acovigilance obligat ions
• St rengthening of signal detect ion com plem ented by stat ist ical analysis
1 Regulat ion (EC) No. 726/ 2004, Direct ive 2001/ 83/ EC 2 Regulat ion (EC) No. 726/ 2004 Art icle 24(2) , paragraph 2 3 Regulat ion (EC) No. 726/ 2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisat ion and supervision of medicinal products for human and veter inary use and establishing a European Medicines Agency 2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 3/ 28
• Elect ronic report ing of EU cases to the World Health Organisat ion Uppsala Monitor ing Cent re.
The EudraVigilance funct ionalit ies to be audited have followed the consultat ion process of the
EMA/ Mem ber States governance st ructure for the im plem entat ion of the pharm acovigilance legislat ion
including the endorsem ent by the EU Telem at ics Managem ent Board, the Pharm acovigilance Risk
Assessm ent Com m it tee and the EMA Managem ent Board.
Following endorsem ent by the EMA Managem ent Board in Decem ber 2013, the EudraVigilance
funct ionalit ies to be audited will provide a basis for EMA to develop a detailed project plan including the
t im elines for im plem entat ion and the plan for the conduct of an independent audit . Moreover, on the
basis of the endorsed funct ionalit ies, detailed business requirem ents will be developed by the EMA in
consultat ion with Mem ber States, which aim to further analyse the end-users’ needs. Following
com plet ion of the system design and development , user test ing with Mem ber States will be perform ed.
The delivery of the agreed funct ionalit ies will be accom panied by end-users t raining. PRAC will be
regular ly updated on the project m ilestones and progress m ade and a PRAC recom m endat ion, as
required by legislat ion, will be sought for the audit that the funct ionalit ies have been delivered.
Based on an independent audit report that takes into account the recom m endat ions of the PRAC, the
EMA Managem ent Board will confirm and announce when full funct ionalit y of the EudraVigilance
database has been achieved and the system m eets the defined funct ional specificat ions. This will br ing
the new requirem ents of the Regulat ion 4 into force.
3 . Data collect ion and data quality
One of the deliverables5 of the pharm acovigilance legislat ion focuses on the elect ronic subm ission of a
core data set on all m edicinal products authorised in the EU by m arket ing authorisat ion holders
(MAHs) . Following publicat ion of a Legal Not ice, 6 and an elect ronic subm ission form at , the EMA
collected these data as part of the eXtended EudraVigilance Medicinal Product Dict ionary (xEVMPD)
with the pr im ary object ive of facilitat ing data analysis and signal detect ion to support bet ter safety
m onitoring for pat ients. The total num ber of m edicinal product subm issions by MAHs during 2013 is
presented in Annex I I I .
From July 2012, the pharm acovigilance legislat ion also int roduced direct report ing of adverse react ions
by pat ients and consum ers in all Mem ber States and enhanced adverse react ion report ing in the
context of post -authorisat ion studies, m edicat ion errors, off- label use and occupat ional exposure. The
num ber of reports related to suspected serious adverse react ions collected and m anaged in
EudraVigilance in 2013 is provided in Annex I I . 2013 shows an increase in the level of report ing
com pared to previous years, and, in part icular, a significant increase in the level of direct pat ient
report ing com pared to previous years.
EudraVigilance cont inues to support the report ing of suspected unexpected serious adverse react ions
(SUSARs) in accordance with EU clinical t r ial legislat ion 7 (see Annex I I ) .
4 Art icle 24 of Regulat ion (EC) No. 726/ 2004 as amended by Regulat ion (EU) No. 1235/ 2010 5 Regulat ion (EC) No. 726/ 2004, Art icle 57(2) , second subparagraph 6 Legal not ice on the implementat ion of Art icle 57(2) , second subparagraph of Regulat ion (EC) No. 726/ 2004 (Doc. Ref. 5 March 2012 EMA/ 505633/ 2011) 7 Direct ive 2001/ 20/ EC of the European Par liament and of the Council of 4 Apr il 2001 on the approximat ion of the laws, regulat ions and adm inist rat ive provisions of the Member States relat ing to the implementat ion of good clinical pract ice in the conduct of clinical t r ials on medicinal products for human use 2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 4/ 28
Qualit y assurance is key to support pharm acovigilance. I n accordance with the pharm acovigilance
legislat ion, the EMA is operat ing procedures that ensure the qualit y and integrity of the inform at ion
collected in EudraVigilance. This refers specifically to the adequate ident ificat ion of m edicinal products
associated with reported adverse react ions, rem oval of duplicate reports, t im ely subm issions of serious
adverse react ions, adherence to coding pract ices and standards as well as adequate case
docum entat ion, which form the basis for successful data analysis and decision m aking to protect public
health.
The EMA’s efforts in im proving data qualit y include t raining provision, detect ing and m erging duplicate
reports, perform ing ICSR data qualit y reviews, providing feedback to individual report ing organisat ions
and conduct ing recoding of adverse react ion reports ut ilising the m edicinal product data of the
XEVMPD. These are sum m arised in Annex IV.
4 . Data analysis
The legislat ion also int roduced clearly defined responsibilit ies for signal detect ion and m anagem ent in
the EU for the Agency and the NCAs. A safety signal refers to inform at ion on one or m ore newly
observed adverse react ions potent ially caused by a m edicine and that warrant further invest igat ion. I f
a safety concern is confirm ed or considered likely to be associated with a m edicinal product , regulatory
act ion m ay be necessary and usually takes the form of an update of the sum m ary of product
characterist ics (Sm PC) and the pat ient leaflet . Som et im es a signal ident ifies safety concerns requir ing
act ion beyond Sm PC changes, e.g. rest r ict ion of use to populat ions in which the benefit - r isk balance
rem ains posit ive or the need for gathering further data from addit ional sources (e.g. observat ional
studies, regist r ies) to bet ter assess the r isk.
EudraVigilance is a key tool in operat ing the new signal m anagem ent processes in the EU. EMA staff
lead on the detect ion and init ial validat ion of safety signals for cent rally authorised m edicinal products
(CAPs) and the NCAs are leading for non-CAPs. Am ong safety signals reviewed by the EMA in 2013,
m ore than 90% originated from EudraVigilance. Details of signal detect ion act ivit ies are presented in
Annex V and progress in term s of signal m anagem ent in the EU is described in Annex VI . Addit ionally,
EMA prepares data output reports (elect ronic react ion m onitor ing reports, e-RMRs) to support
m onitoring of data by NCAs in context of the work-sharing of m onitor ing EV data. Over 19,000 of these
e-RMRs were generated and dist r ibuted to NCAs and EMA staff in 2013.
I n 2013, the PRAC prior it ised and assessed 100 signals, totalling 130 signal discussions. This includes
43 signals detected and validated by the EMA and 57 detected and validated by Mem ber States.
Am ong the signals raised by the EMA, the evaluat ion of 21 signals resulted in changes of the product
inform at ion ( including the dist r ibut ion of a Direct Healthcare Professional Com municat ion in four cases
in order to highlight im portant new inform at ion to prescribers) . The evaluat ion of 14 signals is
current ly at the stage of an assessm ent of data provided by MAHs and the evaluat ion of 7 signals was
concluded following the assessm ent of available data with no further regulatory act ion. For one signal,
a form al review of benefit - r isk in the scope of a referral under art icle 31 of Direct ive 2001/ 83/ EC was
init iated. Overall, the evaluat ion of signals by the PRAC has led to t im ely conclusions of safety reviews
and appropriate act ions for the protect ion of public health.
I n addit ion to the use of EudraVigilance for signal m anagem ent , further em phasis has been put on the
support of pharm acovigilance referral procedures ( incl. urgent union procedures) by providing and
analysing safety data for t he m edicinal products concerned. I n 2013, these act ivit ies focused on
m edicinal products containing the act ive substances alm it rine, codeine, com bined cont racept ives,
cyproterone/ ethinylest radiol, diacerin, dihydrocodeine, dom peridone, est radiol ( topical use) , flupir t ine,
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 5/ 28
nicot inic acid and derivat ives, st ront ium ranelate, solut ions for infusion containing hydroxyethyl starch,
tet razepam , valproate and related substances, zolpidem .
To support the assessm ent of PSURs by Mem ber States, EMA is also providing addit ional data analysis
reports from EudraVigilance and providing t raining to assessors.
5 . Transparency, com m unicat ion and t ra in ing
A key object ive of the new legislat ion is to enhance t ransparency and opt im ise com m unicat ion in
pharm acovigilance. Following the adopt ion of the EudraVigilance Access Policy in 2011, the EMA
launched in 2012 the first phase of the online access to suspected adverse react ion reports8 in all
official languages of the EU on a new public website: www.adrreports.eu. The launch highlights the
im portance of adverse react ion report ing and EudraVigilance in safeguarding public health. The
inform at ion current ly published relates to over 700 medicines and act ive substances authorised
through the cent ralised procedure. I t is planned to extend this website to substances in nat ionally
authorised m edicines subject to worksharing for signal m anagem ent in 2014. The website, available in
all EU languages, was m aintained throughout 2013 with 100% availabilit y.
Signals assessed by the PRAC are publicly available in the context of the publicat ion of the PRAC
m eet ing agendas and m inutes9. I n Septem ber 2013, the Agency started publishing the adopted PRAC
recom m endat ions10 on signals, in order to facilitate their im plem entat ion by the MAHs (e.g. changes to
the product inform at ion) and to increase t ransparency.
The Agency published the list of m edicinal products subject to addit ional m onitor ing 11 in April 2013 and
has m aintained the list prospect ively via m onthly updates. Medicines under addit ional m onitoring have
a black inverted t r iangle displayed in their package leaflet and sum m ary of product character ist ics,
urging healthcare professionals and pat ients to report any suspected adverse react ions via nat ional
report ing systems.
EMA also responds to requests for EudraVigilance data in line with the EudraVigilance Access Policy and
EU legislat ion on access to docum ents12, and in com pliance with EU personal data protect ion13. Details
on requests handled in 2013 are provided in Annex VI I .
I n 2013 the EMA organised four I nform at ion Days for external stakeholders from m edicines regulatory
authorit ies and pharm aceut ical indust ry in relat ion to EudraVigilance and the new internat ional
standards in pharm acovigilance.
Finally, twenty nine EudraVigilance and seven xEVMPD hands-on t raining courses were delivered to
stakeholders in 2013 with 228 users following xEVMPD e- learning t raining. Addit ionally, EVDAS
(EudraVigilance Datawarehouse Analysis System ) t raining was held at the Agency on three occasions,
t raining 44 experts from 10 different NCAs.
8 ht tp: / / www.adrreports.eu/ EN/ index.htm l 9ht tp: / / www.ema.europa.eu/ ema/ index.j sp?curl= pages/ about_us/ document_list ing/ document_list ing_000353.jsp&mid= WC0b01ac05805a21cf 10ht tp: / / www.ema.europa.eu/ ema/ index.j sp?curl= pages/ regulat ion/ document_list ing/ document_list ing_000375.jsp&mid=WC0b01ac0580727d1c 11ht tp: / / www.ema.europa.eu/ ema/ index.j sp?curl= pages/ regulat ion/ document_list ing/ document_list ing_000366.jsp&mid=WC0b01ac058067c852 12 Regulat ion (EC) No. 1049/ 2001 of the European Parliament and of the Council of 30 May 2001 regarding public
access to European Parliament , Council and Commission documents 13 Regulat ion (EC) No. 45/ 2001 of the European Parliament and of the Council of 18 December 2000 on the protect ion of individuals with regard to the processing of personal data by the Community inst itut ions and bodies and on the free movement of such data 2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 6/ 28
6 . Conclusion
EudraVigilance cont inues to be the cent ral pillar to support pharm acovigilance act ivit ies and therefore
cont r ibutes to the protect ion of public health in the EU. The ever increasing num ber of reports received
in EudraVigilance is used for safety m onitor ing of m edicines by the EMA and the Mem ber States,
decision m aking in signals, PSUR and referral procedures by the Agency’s scient ific com m it tees and is
supported by tools for t ransparency for the public, healthcare providers, academ ia and MAHs. I n 2013
t ransparency was st rengthened by the publicat ion of adopted PRAC recom m endat ions for signals and
by establishing the List of m edicinal products subject to addit ional m onitoring.
Further work was carr ied out in 2013 to im prove the data qualit y in EudraVigilance and a further
increase was noted in the num ber of m edicinal product subm issions by the MAHs, establishing the
m ost com plete resource of authorised m edicinal products in the EU.
Following the Managem ent Board endorsem ent of the funct ional specificat ions for the EudraVigilance
database ( “EudraVigilance funct ionalit ies to be audited” ) , the Agency will cont inue to work with the
Mem ber States in 2014 to further define and develop enhanced funct ionalit ies for the benefit of the
stakeholders and st ronger protect ion of public health.
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 7/ 28
Annex I - Sum m ary of EudraVigilance related act ivit ies
I m plem entat ion act iv it ies Status
Operat ion and m aintenance of EudraVigilance by EMA in collaborat ion
with Mem ber States
[ Legal basis: Regulat ion (EC) 726/ 2004, Art icle 24]
Cont inued during 2013
Data qualit y review and duplicate m anagem ent of adverse react ion
reports in EudraVigilance
[ Legal basis: Regulat ion (EC) 726/ 2004, Art icle 24(3) ]
Cont inued during 2013
Collect ion of core data set for all m edicinal products authorised in the
EU in EudraVigilance
[ Legal basis: Regulat ion (EC) 726/ 2004 Art icle 57(2) , second
subparagraph]
Cont inued during 2013
Operat ion of the signal m anagem ent processes based on
EudraVigilance data, including the m onthly provision of e-RMRs to
lead Mem ber State for non-CAPs
[ Legal basis:
• Regulat ion (EC) 726/ 2004, Art icle 28(a) • Direct ive 2001/ 83/ EC, Art icle 107(h)
Com m ission Im plem ent ing Regulat ion (EU) 520/ 212, Art icle 21]
Cont inued during 2013
Access to adverse react ion data held in EudraVigilance for CAPs
ht tp: / / www.adrreports.eu/
[ Legal basis: Regulat ion (EC) 726/ 2004, Art icle 24]
Cont inued during 2013
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 8/ 28
Annex I I – EudraVigilance data - processing netw ork and num ber of suspected adverse react ion repor ts processed by the EudraVigilance database
EudraVigilance data- processing netw ork ( EudraVigilance Gatew ay)
The EudraVigilance data-processing network as referred to in Art icle 24 of Regulat ion (EC) No.
726/ 2004 facilitates the elect ronic exchange of adverse react ion reports between the EMA, m edicines
regulatory authorit ies and MAHs for all m edicines authorised in the European Econom ic Area (EEA) .
This network, known as the EudraVigilance gateway, has been in cont inuous operat ion since Decem ber
2001.
During 2013, a total of 15,747,644 t ransact ions were successfully perform ed by the EudraVigilance
gateway. Figure 1 presents the total num ber of t ransact ions perform ed per m onth during 2013.
0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
1,600,000
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Figure 1 . Total num ber of t ransact ions perform ed per m onth at the level of the EudraVigilance Gateway from 1 January 2013 – 31 Decem ber 2013
EudraVigilance database
For m edicinal products authorised in the EEA, adverse react ions reports are collected from both within
and outside the EEA.
The num bers presented in figure 2 refer to the adverse react ion reports14 received in the post -
authorisat ion m odule. During 2013, an average of 88,474 expedited adverse react ion reports were
received and processed per m onth and subsequent ly m ade available for signal detect ion and data
analysis by EMA and m edicines regulatory authorit ies in the Mem ber States.
14 I n the 2012 report , only "expedited" adverse react ion reports were presented. With the new legislat ion, which has been in force throughout 2013, almost all reports t ransmit ted to EudraVigilance are expedited, so these figures are for all ICSRs/ cases t ransmit ted to EV. 2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 9/ 28
0
20,000
40,000
60,000
80,000
100,000
120,000
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Figure 2 . Num ber of adverse react ion reports processed per m onth in the EudraVigilance database post -authorisat ion m odule in 2013
Figure 3 presents the total num ber of adverse react ion reports15 received in the post -authorisat ion
m odule grouped by EEA and non-EEA for 2013. Each individual case in EudraVigilance refers generally
to a single pat ient ; an individual case is com posed of at least one report , called the init ial report , which
m ight be com plem ented by follow-up reports with updated addit ional inform at ion on the case.
Figure 3 . Num ber of individual cases/ adverse react ion reports processed between January and Decem ber 2013 in the Eudravigilance database post -authorisat ion m odule
15 I n the 2012 report , only "expedited" adverse react ion reports and individual cases were presented. With the new legislat ion, which has been in force throughout 2013, almost all reports t ransm it ted to Eudravigilance are expedited, so these figures are for all ICSRs/ cases t ransmit ted to EV.
256,900370,185
485,471
750,916
0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
I ndividual cases Adverse react ion reports
EEA Non-EEA
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 10/ 28
One very significant effect of the new pharm acovigilance legislat ion was to int roduce an obligat ion for
MAHs & NCAs to inform the Agency about adverse react ions reports received direct ly from pat ients.
Within the EEA, this has led to the num ber of such reports received in EudraVigilance each year
increasing significant ly (and at a higher rate than the increase in the total num ber of cases) since the
ent ry into force of the new legislat ion (13,936 individual cases originat ing from consum ers were
t ransm it ted to EV in 2011, and 30,614 were t ransm it ted to EV in 2013) .
Figure 4 shows the increase in the num ber of EEA cases year-on-year and the proport ionately greater
increase in the num ber of direct pat ient reports, from 2011 ( the last whole year before the ent ry into
force of the new pharm acovigilance legislat ion) to 2013. The num bers have been norm alised to 2011
values ( taking 2011 as 100) to show the com parat ive rates of increase in direct pat ient reports versus
all reports. Table 1, im m ediately below Figure 4, gives both the norm alised and the t rue values.
Figure 4 . The increase in the rate of direct pat ient reports compared to the increase in the rate of all reports from the EEA following the ent ry into force of the new PV legislat ion
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
2011 2012 2013
Direct pat ient cases
0
50,000
100,000
150,000
200,000
250,000
2011 2012 2013
Tota l cases
Number of direct pat ient cases & total cases t ransm it ted to EV each year from 2011 to 2013
Table 1 . The rate of direct pat ient and total EEA case report ing 2011-2013
Year 2011 2012 2013
Reporter
type
Num ber of
cases
% of 2 0 1 1
rates
Num ber of
cases
% of 2 0 1 1
rates
Num ber of
cases
% of 2 0 1 1
rates
Pat ient 13,936 100 20,115 144 30,614 220
Tota l 163,275 100 186,136 114 234,546 144
True16 & normalised values for EEA cases reported to EVPM year-on-year taking 2011 as the baseline for the normalised values
16 These numbers do not take into account the de-duplicat ion work because they are concerned with the increase in the rate of report ing by primary sources and not the rate of t ransmission of ICSRs to EV by MAHs or NCAs, and therefore they are not direct ly comparable to the numbers presented in figures 2 and 3. 2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 11/ 28
By 31 Decem ber 2013, the EudraVigilance database (both post -authorisat ion & clinical t r ials m odules)
held a total of 7,026,537 adverse react ion reports, referr ing to 4,586,491 individual cases (see figure
5) .
1,734,1622,645,858
2,852,329
4,380,679
0
1,000,000
2,000,000
3,000,000
4,000,000
5,000,000
6,000,000
7,000,000
8,000,000
I ndividual cases Adverse react ion reports
EEA Non-EEA
Figure 5 . Total num ber of individual cases/ adverse react ion reports received in the EudraVigilance database from it s incept ion in Decem ber 2001 unt il 31 Decem ber 2013.
E- report ing status for MAHs and sponsors of clinical t r ials
• A total of 758 MAHs (at headquarter level) have sent reports to the EudraVigilance Post -
authorisat ion Module (EVPM) in the period between 1 January 2002 and 31 Decem ber 2013.
• A total of 713 sponsors of clinical t r ials (at headquarter level) have sent reports to the
EudraVigilance Clinical Tr ials Module (EVCTM) in the period between 1 May 2004 and 31 Decem ber
2013.
Tables 2 and 3 below show the total (both expedited and non-expedited) num ber of unique cases and
ICSRs t ransm it ted by MAHs and sponsors to EVPM and EVCTM and the 15-day report ing com pliance of
MAHs and sponsors of clinical t r ials when report ing to EVPM.
15-day report ing com pliance is calculated by subt ract ing the date the ICSR was received by the
EudraVigilance Gateway (EV Message Gateway Date) from the date of receipt of the m ost recent
inform at ion (Receipt Date – ICH E2B(R2)A.1.7) . The receipt date is t reated as day 0, giving the MAH
15 days following that day to t ransm it the reports.
For the re- t ransm ission of reports or iginally t ransm it ted to MAHs by other organisat ions, the receipt
date is the date the MAH received the m ost recent inform at ion from the other organisat ion, not the
date that the other organisat ion received the m ost recent inform at ion from the original reporter.
Nullificat ion and error reports are excluded from the com pliance calculat ions. Only cases flagged by the
MAHs as serious are included in the calculat ions.
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 12/ 28
Table 2 . Num ber of I CSRs and unique cases t ransm it ted by MAHs and sponsors to EVPM and EVCTM during 2013
EV Module Transm ission type Num ber of t ransm issions
EVPM I CSRs 793,176 I ndividual Cases 502,860
EVCTM I CSRs 75,341 I ndividual Cases 28,355
Table 3 . Com bined 15-day report ing com pliance to EVPM for all MAHs and sponsors in 2013.
Percentage of I CSRs t ransm it ted to EVPM by MAHs/ Sponsors w ith in 1 5 days: 9 6 %
E- report ing status for NCAs
• All 31 NCAs have been authorised to enter into product ion with EudraVigilance.
• All NCAs have reported ICSRs to EVPM, except for AFLUV (Liechtenstein) and the Division de la
Pharm acie et des Médicaments (Luxem bourg) , for whom special arrangem ents are in place:
− All ICSRs occurr ing in Liechtenstein are t ransm it ted to EudraVigilance by MAHs.
− The NCA for Luxem bourg has their reports t ransm it ted by the French nat ional agency.
Tables 4 & 5 below shows the total (both expedited and non-expedited) num ber of unique cases and
ICSRs t ransm it ted by NCAs to EVPM and EVCTM and the 15-day report ing com pliance of NCAs when
report ing serious cases to EVPM.
15-day report ing com pliance is calculated by subt ract ing the date the ICSR was received by the
EudraVigilance Gateway (EV Message Gateway Date) from the date of receipt of the m ost recent
inform at ion (Receipt Date – ICH E2B(R2)A.1.7) . The receipt date is t reated as day 0, giving the MAH
15 days following that day to t ransm it the reports.
For the re- t ransm ission of reports or iginally t ransm it ted to NCAs by MAHs, the receipt date is the date
the NCA received the m ost recent inform at ion from the MAH, not the date that the MAH received the
m ost recent inform at ion from the original reporter. Nullificat ion and error reports are excluded from
the com pliance calculat ions. Only cases flagged by the NCA as serious are included in the calculat ions.
The overall NCA 15-day report ing com pliance was 89% , an increase from 2011 & 2012, when it was
84% .
Table 4 . Num ber of I CSRs and unique cases t ransm it ted by NCAs to EVPM & EVCTM during 2013
EV Module Transm ission type Num ber of t ransm issions
EVPM I CSRs 327,925 I ndividual Cases 239,511
EVCTM I CSRs 19,557 I ndividual Cases 12,161
The figures for “ I ndividual Cases” in the table above include the m aster cases t ransm it ted by the EMA.
Table 5 . Com bined 15-day report ing com pliance to EVPM for all NCAs in 2013
Percentage of I CSRs t ransm it ted to EVPM by NCAs within 15 days: 89%
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 13/ 28
During 2013, the following 10 NCAs t ransm it ted SUSARs to EVCTM (SUSARs from other count r ies were
received direct ly from sponsors of clinical t r ials) :
Mem ber State Nat ional Com petent Author it y
BELGIUM FEDERAL AGENCY FOR MEDICINES AND HEALTH
PRODUCTS
CZECH REPUBLIC STATE INSTITUTE FOR DRUG CONTROL
DENMARK DANISH MEDICINES AGENCY
FINLAND FINNI SH MEDI CI NES AGENCY
GERMANY FEDERAL INSTITUTE FOR DRUGS AND MEDI CAL
DEVICES
GERMANY PAUL-EHRLI CH- INSTITUT
ITALY AGENZIA ITALIANA DEL FARMACO
NETHERLANDS COLLEGE TER BEOORDELI NG VAN GENEESMIDDELEN
SWEDEN MEDICAL PRODUCTS AGENCY
UNITED KINGDOM MEDICINES & HEALTHCARE PRODUCTS REGULATORY
AGENCY
EudraVigilance database and support of signal m anagem ent process
A total of 19,330 e-RMRs were generated in 2013 to facilitate the cont inuous m onitoring of the safety
of m edicines by the EMA and m edicines regulatory authorit ies in the EEA.
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 14/ 28
Annex I I I - Tota l num ber of m edicinal product subm issions by MAHs
Tota l num ber of m edicina l product subm issions by MAHs by 3 Feb 2 0 1 4 1 7 in accordance w ith Art icle 5 7 ( 2 ) , second subparagraph of Regulat ion ( E C) 7 2 6 / 2 0 0 4
Total num ber of m edicinal products (counted on the basis of
EudraVigilance codes)
459,290
Total num ber of m arket ing authorisat ion holders ( legal ent it ies)
established in the EU (corresponding to EudraVigilance codes)
3,996
The EudraVigilance code is the level to which a product is defined in the context of the Art icle 57(2) .
I t encom passes the following param eters:
• Nam e of the m edicinal product .
• MAH.
• Authorising Com petent Authorit y.
• Count ry.
• Act ive ingredient (s) .
• St rength(s) .
• Pharm aceut ical form .
• Authorisat ion num ber.
• Authorisat ion procedure.
• Pack size (only if Com petent Authorit y assigns unique m arket ing authorisat ion num ber at package
level) .
17 Please note that this figure is as of 3 Feb 2014 and not 31 Dec 2013. This is due to technical changes made to the database which means it is not possible to give a precise figure as of 31 December 2013. The EMA est imates that the number of MAHs and headquarters would have been almost ident ical as of end-2013 and the number of medicinal products would have been 10-20,000 fewer 2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 15/ 28
Annex I V - EudraVigilance data quality act ivit ies
I n accordance with Regulat ion (EC) No 726/ 2004, Art icle 24(3) , the Agency operates procedures to
ensure the qualit y and integrit y of the inform at ion collected in EudraVigilance. This includes ident ifying
duplicate reports, perform ing the coding of the reported m edicines and reported act ive substances,
and providing feedback on the qualit y of inform at ion sent by NCAs, MAHs and sponsors. The table
below refers to the data qualit y act ivit ies performed by the EMA in 2013.
EudraVigilance data qua lit y act ivit ies in 2 0 1 3
I dent ify ing and m anaging
duplicates
Coding of repor ted m edicines
and act ive substances
Providing feedback on data
qualit y
Num ber of duplicate couples
assessed: 122,308 ( in 2012 this
was 96,298)
Num ber of m edicinal
products/ act ive substances
recoded: 87,660 ( I n 2012 this
was 82,076)
Total num ber of organisat ions
subject to data qualit y review:
166 ( I n 2012 this was 216)
Num ber of ‘m aster’ reports
generated based on duplicated
data: 65,906 ( I n 2012 this was
83,393)
Num ber of adverse react ion
reports recoded: 555,798
( referr ing to 275,852 individual
cases) .
I n 2012 616,001 adverse
react ion reports were recoded,
referr ing to 356,000 individual
cases.
The overall rate of duplicates reported to EudraVigilance since it s launch is est im ated at about 8% .
This includes “different -sender” duplicates as well as “sam e-sender” duplicates. “Sam e-sender”
duplicates are those were all duplicates in the cluster were t ransm it ted to EudraVigilance by the same
organisat ion (NCAs, MAHs, sponsors) .
I n accordance with Direct ive 2001/ 83/ EC, Art icles 107(5) and 107a(3) , the Agency is collaborat ing
with MAHs and NCAs to detect and elim inate duplicate suspect adverse react ion reports. To this end,
when suspected duplicate suspect adverse react ion reports are detected in EudraVigilance and both of
the suspected duplicates are from the sam e sender, the Agency will send inform at ion on these
suspected ‘sam e-sender’ duplicates to the organisat ion which t ransm it ted these cases to
EudraVigilance and ask them to m anage them appropriately.
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 16/ 28
Annex V – Signal detect ion
I n 2013, the total num ber of signals reviewed increased by approx. 11% com pared to 2012. This
parallels the increased num ber of ICSRs received in EudraVigilance, the increasing use of standardised
MedDRA queries (SMQs) for analysis (and subsequent ly a higher num ber of preferred term s which are
t racked) as well as the im plem entat ion of the list of designated m edical events (DMEs) in the e-RMR
and addit ional categories which warrant pr ior it y screening ( i.e. m ost relevant react ions term s/ DMEs,
fatal, paediat ric reports etc.) in 2012.
OVERVI EW 2 0 1 3 2 0 1 2 2 0 1 1 2 0 1 0 2 0 0 9 2 0 0 8
Total 2,449 2,213 1,586 2,054 1,704 1,327
Difference vs previous year 236 627 -468 350 377 Ref.
Difference % 10.7% 39.5% -22.8% 20.5% 28.4% Ref.
Overall, 91% of potent ial signals or iginated from EudraVigilance, with other sources account ing for:
5% from the scient ific literature, 3% from com m unicat ions received from other Regulatory Agencies
worldwide (52 from MHLW/ PMDA, 15 from the FDA, 5 from the WHO and 4 from EMCDDA) and 1%
from other sources. The overview of signals validat ion by act ion taken is provided below:
Act ion taken Num ber of signals
Jan - Dec 2 0 1 3
% of
tota l
Num ber of signals
Jan - Dec 2 0 1 2
% of
tota l
Closed 2126 87% 1869 84%
Ongoing 211 9% 195 9%
Monitored 69 3% 97 4%
Prior it ised and analysed by PRAC 43 2% 52* 2%
Total 2449 100% 2213 100%
* reflects the num ber of signals com m unicated to Rapporteurs by the EMA in 2012 (pr ior to, and after
the inaugurat ion of the PRAC)
I n total, 2,449 potent ial signals were reviewed in 2013 by the Agency. 43 signals validated and
com m unicated to the Rapporteurs by the Agency were priorit ised and analysed by the PRAC during
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 17/ 28
2013. Of note, 2 of these signals had been under m onitor ing by the signal validat ion team at the
Agency in 2012, 8 were prom pted by the scient ific literature and 5 by inform at ion received from other
regulatory authorit ies (3, 5 and 6, respect ively in 2012) .
At the t im e of this report , approxim ately half of the 43 signals handled by the PRAC (n= 21) led to
recom m endat ion for changes to the product inform at ion, either direct ly (n= 7) or following a
cum ulat ive review (n= 14) , providing inform at ion to pat ients and healthcare professionals on the safe
use of these products. For four signals, this also included the dist ribut ion of Direct Healthcare
Professional Com m unicat ions (DHPC) to increase awareness about the new safety inform at ion. The
evaluat ion of 14 signals following the recom m endat ion for a cum ulat ive review is current ly on-going.
The evaluat ion of seven signals was closed with no further regulatory act ion required, with the rout ine
pharm acovigilance act ivit ies deem ed sat isfactory for further follow-up of these signals. One signal led
to a form al evaluat ion of the benefit - r isk balance via an Art icle 31 referral.
Addit ionally, 69 signals (approx. 3% ) were kept under m onitoring (as of end of Dec 2013) . I f a signal
is m onitored, in pr inciple all new cases of that react ion sent to EudraVigilance are reviewed.
Overview of signals validated by the Agency pr ior it ised and assessed by the PRAC
Since the establishm ent of the PRAC in July 2012, a new signal m anagem ent process has been in
place. Signals are com m unicated to PRAC m em bers who confirm the validit y of the signals in line with
the new legislat ion and the Guideline on good pharm acovigilance pract ices: Module IX – Signal
m anagem ent . Confirm ed signals are t ransm it ted to the PRAC for pr ior it isat ion and analysis. I n line with
the new legislat ion’s aim of increasing t ransparency and com m unicat ion in pharm acovigilance, agendas
and m inutes of the PRAC are being m ade public. Since Septem ber 2013 this also includes the
recom m endat ions on signals as adopted by the Comm it tee, and can be found here.
An overview of validated signals is provided in the following tables, including the latest regulatory
status as of 21 January 2014. When the outcom e of an init ial recom m endat ion is already known, both
are noted sequent ially.
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 18/ 28
Drug I ssue Latest status or outcom e
Adalim um ab Derm atom yosit is cum ulat ive review: update of
product inform at ion
Adalim um ab Im m une Reconst itut ion I nflam m atory
Syndrom e ( IRIS)
cum ulat ive review
Aflibercept Blindness cum ulat ive review
Agents act ing on the renin-
angiotensin system
Efficacy and safety of dual blockade
of the renin-angiotensin system :
m eta-analysis of random ised t r ials
Art icle 31 referral: evaluat ion
ongoing
Agom elat ine QT prolongat ion cum ulat ive review: no
regulatory act ion ( rout ine
pharm acovigilance)
Bevacizum ab Anaphylact ic shock cum ulat ive review: no
regulatory act ion ( rout ine
pharm acovigilance)
Brentuxim ab Vedot in Pulm onary toxicit y cum ulat ive review: update of
product inform at ion
Capecitabine Acute renal failure cum ulat ive review: update of
product inform at ion
Capecitabine Convulsion cum ulat ive review
Cinacalcet Fatal case with severe hypocalcem ia
in a pediat r ic clinical study
update of product inform at ion
and DHPC
Clopidogrel Acquired haem ophilia A cum ulat ive review: update of
product inform at ion
Clopidogrel Cross- react ivit y between clopidogrel
and t iclopidine am ong pat ients with
previous allergic and/ or haem atologic
react ions to one of these products
update of product inform at ion
Clopidogrel Eosinophilic pneum onia cum ulat ive review: update of
product inform at ion
Denosum ab Vasculit is cum ulat ive review
Dexm edetom idine I nfant ile apnoeic at tack cum ulat ive review
Docetaxel Serious and fatal drug interact ions
involving CYP3A4 (grapefruit j uice
and dronedarone)
cum ulat ive review: update of
product inform at ion
Docetaxel Throm bot ic m icroangiopathy cum ulat ive review: no
regulatory act ion ( rout ine
pharm acovigilance)
Duloxet ine I nteract ion with ar ipiprazole -
serotonin syndrom e
cum ulat ive review: no
regulatory act ion ( rout ine
pharm acovigilance)
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 19/ 28
Drug I ssue Latest status or outcom e
Duloxet ine I nteract ion with linezolid leading to
serotonin syndrom e
update of product inform at ion
Efavirenz; Em t ricitabine,
efavirenz, tenofovir
I nteract ion with Ginkgo biloba update of product inform at ion
Etanercept Derm atom yosit is cum ulat ive review: update of
product inform at ion
Exenat ide I nject ion site abscess and cellult is cum ulat ive review
Exenat ide, Liraglut ide Cholecyst it is and cholelithiasis cum ulat ive review
Exenat ide, Liraglut ide Gast rointest inal stenosis and
obst ruct ion
cum ulat ive review: update of
product inform at ion
Filgrast im , Pegfilgrast im Capillary leak syndrom e, cytokine
release syndrom e
cum ulat ive review: update of
product inform at ion and DHPC
Fondaparinux Heparin- induced throm bocytopenia cum ulat ive review: no
regulatory act ion ( rout ine
pharm acovigilance)
Glycopyrronium Angioedem a cum ulat ive review
Hum an papillom avirus
vaccine [ t ypes 16, 18]
( recom binant , adjuvanted,
adsorbed)
Com plex regional pain syndrom e cum ulat ive review
Hum an papillom avirus
vaccine [ t ypes 6, 11, 16,
18] ( recom binant ,
adsorbed)
Com plex regional pain syndrom e cum ulat ive review
Inflixim ab Im m une Reconst itut ion I nflam m atory
Syndrom e ( IRIS)
cum ulat ive review
Leflunom ide Drug React ion with Eosinophilia and
System ic Sym ptom s (DRESS)
update of product inform at ion
Leflunom ide Myosit is cum ulat ive review: no
regulatory act ion ( rout ine
pharm acovigilance)
Lenograst im (System ic) capillary leak syndrom e
(CLS)
cum ulat ive review: update of
product inform at ion and DHPC
Levet iracetam Hyponat raem ia and inappropriate
ant idiuret ic horm one secret ion
(SIADH)
cum ulat ive review: update of
product inform at ion
Mirabegron Urinary retent ion cum ulat ive review
Orlistat Pharm acokinet ic drug interact ion (at
absorpt ion) with highly act ive
ant iret roviral therapy(HAART) leading
to loss of HAART efficacy
cum ulat ive review: update of
product inform at ion
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 20/ 28
Drug I ssue Latest status or outcom e
Sitaglipt in,
Sitaglipt in/ m et form in
Angioedem a due to interact ion
between sitaglipt in and ACE inhibitors
cum ulat ive review
Som at ropin Convulsions cum ulat ive review: no
regulatory act ion ( rout ine
pharm acovigilance)
Tem ozolom ide Hepat ic failure cum ulat ive review: update of
product inform at ion and DHPC
Teriparat ide Anaphylact ic shock update of product inform at ion
Thalidom ide Posterior Reversible Encephalopathy
Syndrom e (PRES)
cum ulat ive review: update of
product inform at ion
Ticagrelor Food interact ion with grapefruit j uice update of product inform at ion
Vem urafenib Renal failure cum ulat ive review
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 21/ 28
Annex VI - Signal m anagem ent in the EU
Signal m anagem ent is the procedure which covers all the steps from the detect ion of a new signal to
it s evaluat ion by the appropriate scient ific com mit tee, including the signal validat ion, signal
confirm at ion, signal analysis and prior it izat ion, signal assessm ent , recom m endat ion for act ion and the
exchange of inform at ion between the relevant part ies.
Following the experience from the Pilot of signal m anagem ent in the EU, further progress in signal
m anagem ent has been m ade through the Signal Management Review Technical Working Group, a
collaborat ion group for cont inuous process im provement between the EMA and the MSs in the
European Medicines Regulatory Network. Three areas were ident ified for facilitat ion of signal
m anagem ent in the EU: Signal m anagem ent tools and processes, Methodological guidance and Signal
detect ion m ethods. The following act ions were com pleted in 2013:
• Standardised tem plates for assessm ent of signal data and the corresponding form for the PRAC
recom m endat ion were developed for the use by the network.
• A Quest ions & answers on signal m anagem ent docum ent (EMA/ 261758/ 2013) was published
on the EMA website to provide procedural guidance for MAHs regarding handling of signals
discussed at PRAC and any follow-up act ions that m ay arise.
• The Agency started publishing the signal recom m endat ions adopted by the PRAC on a
dedicated sect ion of the EMA website18 to facilitate implem entat ion of the PRAC
recom m endat ions by the MAHs and to increase t ransparency.
• The European Pharm acovigilance I ssues Tracking Tool database was am ended following the
im plem entat ion of the new pharm acovigilance legislat ion, to accom m odate the new steps in
signal m anagem ent process in line with the new legislat ion and to allow for a m ore com plete
t racking of the signal life cycle. The user guide was updated accordingly.
• I ntegrat ion of signal procedures into the Agency’s t racking system s was achieved, to allow for
t racking of signal procedures and their corresponding t im etables. Further work for nat ionally
authorised products is foreseen in the future.
• Further research into stat ist ical signal detect ion m ethods was carr ied out , with a view to
update the exist ing Guideline on the use of stat ist ical signal detect ion m ethods in EVDAS (Doc.
Ref. EMEA/ 106464/ 2006) .
18ht tp: / / www.ema.europa.eu/ ema/ index.j sp?curl= pages/ regulat ion/ document_list ing/ document_list ing_000375.jsp&mid=WC0b01ac0580727d1c 2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 22/ 28
Annex VI I - Requests for inform at ion and docum ents
Seventy- two requests were answered in 2013, com pared to 80 in 2012. Whereas the total num ber has
rem ained sim ilar, an increase was observed for requests from the general public, HCPs, the MAHs and
non-EU regulatory authorit ies. The drop in requests from journalists was observed already in 2012 and
cont inued throughout 2013. This m ay be due to the proact ive publicat ion of adverse drug react ion data
for CAPs at www.adrreports.eu, which started on 31 May 2012. Data from seven requests were used to
support the decision m aking in the context of European referral procedures ( listed below) .
The m edian response t im e in 2013 was 23 days ( range 0-182 days) com pared to 18 days in 2012
( range 0-100 days) . The t im e of response is subject to different factors such as the urgency of the
request , the com plexity of the search needed and the agreed t imeliness especially for internal EU
requests. 35% of the requests were answered within 14 days, 61% within 1 m onth and 86% within
two m onths which is a decrease com pared with 2012 (49% , 68% and 95% , respect ively) and reflects
the increase in com plexity of requests and num ber of products/ react ions requested.
An overview is provided below by type of request , authorisat ion type of requested product (s) ,
requester t ype, therapeut ic group of requested product (s) and origin count ry (external requests only) .
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 23/ 28
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 24/ 28
Overview of requests handled in 2 0 1 3
Type of requester Drug/ substance I ssue Type of request
I nternal EU
Regulatory Network
Acetylsalicylic acid ADRs for acetylsalicylic acid in
low dose
Access to inform at ion
and docum ents
MAH Agom elat ine Angioedem a Access to docum ents
Law firm Alendronate
Flutam ide
Om eprazole
Rim onabant
Alendronate - ONJ
Flutam ide - Death
Om eprazole - Hepat it is and
Hepatotoxicit y
Rim onabant - Depression,
m anic depression and m ental
disorders
Access to inform at ion
I nternal EU
Regulatory Network
Aliskiren Data of use in paediat r ic
populat ion
Access to inform at ion
and docum ents
I nternal EU
Regulatory Network
All substances in the
database
PML Access to inform at ion
General Public Allopurinol ICSRs subm it ted within the
Skin SOC
Access to inform at ion
Non-EU Regulatory
Authorit ies
Andrographis
paniculata (Burm .f.)
Nees.
All ICSR subm it ted to the
database
Access to inform at ion
I nternal EU
Regulatory Network
Ant idiabet ic
m edicines
Pancreat it is and pancreat ic
cancer
Access to inform at ion
Non-EU Regulatory
Authorit ies
Arcoxia - etor icoxib - Fatal outcom es
- Cardiac disorders
- Cent ral nervous system
- Vascular disorders
Access to inform at ion
and docum ents
Academ ia Asthm a m edicat ions
in children
All ADRs reported in children
subm it ted from 2007 to 2011
Access to docum ents
I nternal EU
Regulatory Network
Atosiban Contam inat ion issues Access to inform at ion
MAH Avast in -
bevacizum ab
Anaphylact ic shock Access to docum ents
I nternal EU
Regulatory Network
Avast in -
Bevacizum ab
Ocular use Access to inform at ion
I nternal EU
Regulatory Network
Azithrom ycin Fatal arrhythm ias Access to docum ents
Journalist Bedaquiline All ADRs reported to the
database
Access to inform at ion
I nternal EU
Regulatory Network
Benzyl Alcohol Gasping syndrom e Access to inform at ion
I nternal EU
Regulatory Network
Biphasic insulin
aspart
Hom ogeneity issue Access to inform at ion
Journalist Cabazitaxel Medicat ion errors Access to inform at ion
Non-EU Regulatory
Authorit ies
Clopidogrel Acquired haem ophilia A Access to docum ents
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 25/ 28
Type of requester Drug/ substance I ssue Type of request
I nternal EU
Regulatory Network
Codeine Data to support the Referral
procedure
Access to inform at ion
General Public Colchicine and
m ethot rexate
All ICSRs subm it ted to the
database
Access to inform at ion
I nternal EU
Regulatory Network
Com bined oral
cont racept ives
Data to support the Referral
procedure
Access to inform at ion
I nternal EU
Regulatory Network
Cont racept ives Em bolic and throm bot ic events Access to docum ents
I nternal EU
Regulatory Network
Cyproterone Data to support the Referral
procedure
Access to inform at ion
I nternal EU
Regulatory Network
Dext rom ethorphan ADRs reported in the EU Access to inform at ion
Academ ia Diabet ic m edicines Research Protocol Access to inform at ion
I nternal EU
Regulatory Network
Diacerein Data to support the Referral
procedure
Access to inform at ion
MAH Digoxin
Am it r iptyline
Details of all the ICSRs
subm it ted
Access to docum ents
Academ ia Dom peridone All ICSRs subm it ted to the
database
Access to inform at ion
and docum ents
I nternal EU
Regulatory Network
Dom peridone Data to support the Referral
procedure
Access to inform at ion
Journalist Drospirenone All ADRs reported to the
database
Access to inform at ion
and docum ents
I nternal EU
Regulatory Network
Efavirenz Cancer reports and bir th
defects
Access to inform at ion
General Public Enoxaparin Cardiovascular disorders Access to inform at ion
Journalist Exenat ide
Liraglut ide
Lixisenat ide
Sitaglipt in
Saxaglipt in
Linaglipt in
Vildaglipt in
Cancer of the thyroid and
pancreat ic glands
Access to inform at ion
I nternal EU
Regulatory Network
Fluenz and Fluariz Medicat ion errors Access to inform at ion
I nternal EU
Regulatory Network
Flupirt ine Data to support the Referral
procedure
Access to inform at ion
European
Parliam ent
Gardasil Mult iple Sclerosis Access to inform at ion
and docum ents
I nternal EU
Regulatory Network
Gilenya - fingolim oid PML Access to inform at ion
I nternal EU
Regulatory Network
Gilenya - fingolim oid PML Access to inform at ion
and docum ents
General Public Havrix, Engerix and
Twinrix
Mult iple sclerosis Access to docum ents
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 26/ 28
Type of requester Drug/ substance I ssue Type of request
I nternal EU
Regulatory Network
Heparins Trend analysis of ADRs Access to inform at ion
I nternal EU
Regulatory Network
Hexoprenaline All ICSRs subm it ted to the
database
Access to inform at ion
and docum ents
Non-EU Regulatory
Authorit ies
HPV Vaccines Com plex regional pain
syndrom e
Access to inform at ion
MAH Hydroxyethyl starch Total of ICSRs and cases
reports with fatal outcom e
Access to inform at ion
I nternal EU
Regulatory Network
I notuzum ab
ozogam icin
Veno-occlusive disease and
hepatotoxicit y
Access to inform at ion
and docum ents
I nternal EU
Regulatory Network
I nterferon beta Risk of collapsing focal
segm ental glom erulosclerosis
Access to inform at ion
Non-EU Regulatory
Authorit ies
I nt ralipid Reports of ADRs subm it ted for
an specific form ulat ion
Access to inform at ion
and docum ents
MAH Lopinavir/ r itonavir
and quet iapine
Drug interact ion between
protease inhibitors and
quet iapine
Access to docum ents
HCP Magnesium sulfate,
thiam ine and
procaine
All ADRs reported to the
database
Access to inform at ion
and docum ents
MAH Mirtazapine Pancreat it is Access to docum ents
Other EU Agencies MMR Vaccines I nform at ion on ADRs of MMR
vaccines in adults.
Access to inform at ion
Academ ia Mult iple substances Research protocol Access to inform at ion
General Public Natalizum ab PML Access to docum ents
I nternal EU
Regulatory Network
Nicot inic acid Data to support the Referral
procedure
Access to inform at ion
I nternal EU
Regulatory Network
Num eta G13% E Hyperm agnesaem ia in preterm
infants
Access to inform at ion
HCP Paracetam ol Allergic react ions Access to inform at ion
and docum ents
Other EU Agencies Phenibut All ICSRs subm it ted to the
database
Access to inform at ion
I nternal EU
Regulatory Network
Privigen Haem olysis Access to inform at ion
I nternal EU
Regulatory Network
Ranbaxy products Qualit y issues Access to inform at ion
Consultancy Resorcinol Endocrine, skin and
subcutaneous disorders
Access to inform at ion
and docum ents
MAH Sert raline Growth retardat ion in children
and adolescents
Access to docum ents
HCP Sodium picosulphate
+ m agnesium cit rate
Polyethylene glycol
Convulsions, seizures and
epilepsy
Access to inform at ion
and docum ents
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 27/ 28
Type of requester Drug/ substance I ssue Type of request
(m acrogol) +
ascorbic
acid/ ascorbate
Oral polyethylene
glycol (m acrogol)
MAH St ront ium ranelate Atypical fem ur fracture Access to inform at ion
and docum ents
I nternal EU
Regulatory Network
Synflor ix I nform at ion on case reports
from clinical t r ials
Access to inform at ion
Non-EU Regulatory
Authorit ies
Tacrolim us Medicat ion errors Access to inform at ion
I nternal EU
Regulatory Network
Thiocolchicoside Genotoxicit y Access to inform at ion
and docum ents
I nternal EU
Regulatory Network
Tolcapone,
natalizum ab and
aloset ron
Tolcapone - Hepat ic disorders
Natalizum ab - PML
Aloset ron - Gast rointest inal
disorders
Access to inform at ion
I nternal EU
Regulatory Network
Tredapt ive
( laropiprant , nicot inic
acid)
All ADRs reported Access to inform at ion
Other EU Agencies Tropicam ide Misuse and abuse Access to inform at ion
HCP Valproate Middle or/ and inner ear
m alform at ion
Access to inform at ion
Non-EU Regulatory
Authorit ies
Xaluprine -
m ercaptopurine
Medicat ion errors Access to I nform at ion
MAH Yellox - brom fenac Cardiac failure Access to docum ents
2013 Annual Report on EudraVigilance for the European Par liament , the Council and the Com m ission EMA/ 145085/ 2014 Page 28/ 28