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04 April 2014
EMA/ 145085/ 2014
I nspect ions and Hum an Medicines Pharm acovigilance
2013 Annual Report on EudraVigilance for t he European
Parliam ent , t he Council and t he Com m ission
Report ing period: 1 January t o 31 Decem ber 2013
7 West ferry Cir cus Canary Wharf London E14 4HB Unit ed Kingdom
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E- m a il info@em a.europa.eu W e bsit e ww w.em a.europa.eu
An agency of t he Eur opean Union
© European Medicines Agency, 2014. Reproduct ion is aut horised prov ided t he sour ce is acknow ledged.
Ta ble of Con t ent s
1 . I n t r odu ct ion ............................................................................................ 3
2 . D e ve lopm e n t of n e w fu n ct ion a lit ie s ........................................................ 3
3 . D a t a colle ct ion a n d da t a qu a lit y .............................................................. 4
4 . D a t a a n a lysis ........................................................................................... 5
5 . Tr a n spa r e n cy, com m u n ica t ion a n d t r a in in g ............................................. 6
6 . Con clusion ............................................................................................... 7
An n ex I - Su m m a r y of Eu dr a Vigila n ce r e la t e d a ct ivit ie s .............................. 8
An n ex I I – Eu dr a Vigila n ce da t a - pr oce ssin g n et w or k a n d nu m be r of
suspe ct e d a dver se r e a ct ion r e por t s pr oce sse d by t h e Eu dr a Vigila n ce
da t a ba se ...................................................................................................... 9
EudraVigilance dat a- processing net wor k ( EudraVigilance Gat eway) ................................... 9
EudraVigilance dat abase .............................................................................................. 9
E- r eport ing st at us for MAHs and sponsor s of clinical t rials .............................................. 12
E- r eport ing st at us for NCAs ........................................................................................ 13
EudraVigilance dat abase and support of signal m anagem ent process ............................... 14
An n ex I I I - Tot a l n u m be r of m e dicin a l pr odu ct su bm ission s by M AH s ....... 1 5
An n ex I V - Eu dr a Vigila n ce da t a qu a lit y a ct ivit ie s ...................................... 1 6
An n ex V – Sign a l de t e ct ion ........................................................................ 1 7
Ov erview of signals validat ed by t he Agency priorit ised and assessed by t he PRAC............ 18
An n ex VI - Sign a l m a n a ge m e n t in t h e EU .................................................. 2 2
An n ex VI I - Re qu est s for infor m a t ion a n d docu m en t s ............................... 2 3
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
Page 2/ 28
1 . I n t rodu ct ion
The European Medicines Agency ( EMA) works wit hin t he European Regulat ory Net work t o support t he
m onit oring of t he safet y of m edicines. The EMA's m ain responsibilit ies in t his area include t he
coordinat ion of t he European pharm acovigilance syst em , t he provision of inform at ion on t he safe and
effect ive use of m edicines and operat ing and m aint aining EudraVigilance ( EV) and t he EudraVigilance
Dat a Analysis Syst em ( EVDAS) . Bot h EMA and m edicines regulat ory aut horit ies in Mem ber St at es are
required by legislat ion t o cont inuously m onit or t he adverse react ion dat a report ed t o EudraVigilance t o
det erm ine whet her t here are new risks or know n risk s which have changed and whet her t hose risks
have an im pact on t he overall benefit - risk balance of a m edicine.
I n t he cont ext of t he im plem ent at ion of t he new phar m acovigilance legislat ion 1 , m aj or em phasis is
being been put on furt her st rengt hening t he role of EudraVigilance as regards sim plifying adverse
react ion report ing, collect ing adverse react ions report ed by pat ient s and consum ers ( as well as t hose
from healt hcare professionals) , det ect ing new risks, m onit oring known or pot ent ial risks, risk
assessm ent by t he Pharm acovigilance Risk Assessm ent Com m it t ee ( PRAC) and increasing t ransparency
by providing st akeholders wit h adequat e access t o adverse react ion dat a and analysis ( via EVDAS and
elect ronic React ion Monit oring Report s, eRMRs) .
I n com pliance wit h t he EU pharm acovigilance legislat ion 2 , t he EMA has prepared t his annual report for
t he European Parliam ent , t he Council and t he Com m ission t o provide a sum m ary of t he EudraVigilance
relat ed act ivit ies t hat t he EMA undert ook in 2013 wit hin t he EU regulat ory net work and wit h
st akeholders.
2 . D e velopm en t of ne w fun ct ion a lit ie s
The revised pharm aceut ical legislat ion foresees furt her im provem ent s in t he funct ionalit y of EV. I n
accordance wit h Art icle 24 of Regulat ion ( EC) 726/ 2004 3 , t he Agency, in collaborat ion wit h t he Mem ber
St at es and t he Com m ission, shall draw up t he funct ional specificat ions for t he EudraVigilance dat abase
( hereaft er referred t o as “ EudraVigilance funct ionalit ies t o be audit ed” ) t oget her wit h a t im efram e for
t heir im plem ent at ion. The EudraVigilance funct ionalit ies t o be audit ed focus on t he key deliverables
which will benefit Mem ber St at es, pharm aceut ical indust ry and furt her st rengt hen t he prot ect ion of
public healt h. More specifically, t hey will deliver:
•
Sim plificat ion of adverse r eact ion report ing
•
High- qualit y and int egrit y of pharm acovigilance inform at ion held in EudraVigilance
•
Adapt at ion t o t echnical and scient ific progress by im plem ent at ion of t he I SO st andards for
individual case safet y report s and ident ifying m edicines ( subj ect t o I SO t im elines)
•
Full im plem ent at ion of t he EudraVigilance Access Policy including access by m ar ket ing
aut horisat ion holders t o t he ext ent necessary t o fulfil t heir pharm acovigilance obligat ions
•
St rengt hening of signal det ect ion com plem ent ed by st at ist ical analysis
1
Regulat ion ( EC) No. 726/ 2004, Direct ive 2001/ 83/ EC
Regulat ion ( EC) No. 726/ 2004 Art icle 24( 2) , paragraph 2
3
Regulat ion ( EC) No. 726/ 2004 of t he European Parliam ent and of t he Council of 31 March 2004 laying dow n Com m unit y
procedures for t he aut horisat ion and supervision of m edicinal product s for hum an and vet erinary use and est ablishing a
European Medicines Agency
2
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
Page 3/ 28
•
Elect ronic report ing of EU cases t o t he World Healt h Organisat ion Uppsala Monit oring Cent re.
The EudraVigilance funct ionalit ies t o be audit ed have followed t he consult at ion process of t he
EMA/ Mem ber St at es governance st ruct ure for t he im plem ent at ion of t he pharm acovigilance legislat ion
including t he endorsem ent by t he EU Telem at ics Managem ent Board, t he Pharm acovigilance Risk
Assessm ent Com m it t ee and t he EMA Managem ent Board.
Following endorsem ent by t he EMA Managem ent Board in Decem ber 2013, t he EudraVigilance
funct ionalit ies t o be audit ed will provide a basis for EMA t o develop a det ailed proj ect plan including t he
t im elines for im plem ent at ion and t he plan for t he conduct of an independent audit . Moreover, on t he
basis of t he endorsed funct ionalit ies, det ailed business requirem ent s will be developed by t he EMA in
consult at ion wit h Mem ber St at es, which aim t o furt her analyse t he end- users’ needs. Following
com plet ion of t he syst em design and developm ent , user t est ing wit h Mem ber St at es will be perform ed.
The delivery of t he agreed funct ionalit ies will be accom panied by end- users t raining. PRAC will be
regularly updat ed on t he proj ect m ilest ones and progress m ade and a PRAC recom m endat ion, as
required by legislat ion, will be sought for t he audit t hat t he funct ionalit ies have been delivered.
Based on an independent audit report t hat t akes int o account t he recom m endat ions of t he PRAC, t he
EMA Managem ent Board w ill confirm and announce w hen full funct ionalit y of t he EudraVigilance
dat abase has been achieved and t he syst em m eet s t he defined funct ional specificat ions. This will bring
t he new requirem ent s of t he Regulat ion 4 int o force.
3 . D a t a colle ct ion a n d da t a qu a lit y
One of t he deliverables 5 of t he pharm acovigilance legislat ion focuses on t he elect ronic subm ission of a
core dat a set on all m edicinal product s aut horised in t he EU by m ar ket ing aut horisat ion holders
( MAHs) . Following publicat ion of a Legal Not ice, 6 and an elect ronic subm ission form at , t he EMA
collect ed t hese dat a as part of t he eXt ended EudraVigilance Medicinal Product Dict ionary ( xEVMPD)
wit h t he prim ary obj ect ive of facilit at ing dat a analysis and signal det ect ion t o support bet t er safet y
m onit oring for pat ient s. The t ot al num ber of m edicinal product subm issions by MAHs during 2013 is
present ed in Annex I I I .
From July 2012, t he phar m acovigilance legislat ion also int roduced direct report ing of adverse react ions
by pat ient s and consum ers in all Mem ber St at es and enhanced adverse react ion report ing in t he
cont ext of post - aut horisat ion st udies, m edicat ion errors, off- label use and occupat ional exposure. The
num ber of report s relat ed t o suspect ed serious adverse react ions collect ed and m anaged in
EudraVigilance in 2013 is provided in Annex I I . 2013 shows an increase in t he level of report ing
com pared t o previous year s, and, in part icular, a significant increase in t he level of direct pat ient
report ing com pared t o previous years.
EudraVigilance cont inues t o support t he report ing of suspect ed unexpect ed serious adverse react ions
( SUSARs) in accordance wit h EU clinical t rial legislat ion 7 ( see Annex I I ) .
4
Art icle 24 of Regulat ion ( EC) No. 726/ 2004 as am ended by Regulat ion ( EU) No. 1235/ 2010
Regulat ion ( EC) No. 726/ 2004, Art icle 57( 2) , second subparagraph
6
Legal not ice on t he im plem ent at ion of Art icle 57( 2) , second subparagraph of Regulat ion ( EC) No. 726/ 2004 ( Doc. Ref. 5
March 2012 EMA/ 505633/ 2011)
5
7
Direct ive 2001/ 20/ EC of t he European Parliam ent and of the Council of 4 April 2001 on t he approxim at ion of t he
laws, regulat ions and adm inist rat ive provisions of t he Mem ber St at es relat ing t o t he im plem ent at ion of good clinical
pract ice in t he conduct of clinical t rials on
m edicinal product s for hum an use
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
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Qualit y assurance is key t o support pharm acovigilance. I n accordance wit h t he pharm acovigilance
legislat ion, t he EMA is operat ing procedures t hat ensure t he qualit y and int egrit y of t he inform at ion
collect ed in EudraVigilance. This refers specifically t o t he adequat e ident ificat ion of m edicinal product s
associat ed wit h report ed adverse react ions, rem oval of duplicat e report s, t im ely subm issions of serious
adverse react ions, adherence t o coding pract ices and st andards as well as adequat e case
docum ent at ion, which for m t he basis for successful dat a analysis and decision m aking t o prot ect public
healt h.
The EMA’s effort s in im proving dat a qualit y include t raining provision, det ect ing and m erging duplicat e
report s, perform ing I CSR dat a qualit y reviews, providing feedback t o individual report ing organisat ions
and conduct ing recoding of adverse react ion report s ut ilising t he m edicinal product dat a of t he
XEVMPD. These are sum m arised in Annex I V.
4 . D a t a a n alysis
The legislat ion also int roduced clearly defined responsibilit ies for signal det ect ion and m anagem ent in
t he EU for t he Agency and t he NCAs. A safet y signal r efers t o inform at ion on one or m ore newly
observed adverse react ions pot ent ially caused by a m edicine and t hat warrant furt her invest igat ion. I f
a safet y concern is confirm ed or considered likely t o be associat ed wit h a m edicinal product , regulat ory
act ion m ay be necessary and usually t akes t he form of an updat e of t he sum m ary of product
charact erist ics ( Sm PC) and t he pat ient leaflet . Som et im es a signal ident ifies safet y concerns requiring
act ion beyond Sm PC changes, e.g. rest rict ion of use t o populat ions in which t he benefit - risk balance
rem ains posit ive or t he need for gat hering furt her dat a from addit ional sources ( e.g. observat ional
st udies, regist ries) t o bet t er assess t he risk.
EudraVigilance is a key t ool in operat ing t he new signal m anagem ent processes in t he EU. EMA st aff
lead on t he det ect ion and init ial validat ion of safet y signals for cent rally aut horised m edicinal product s
( CAPs) and t he NCAs are leading for non- CAPs. Am ong safet y signals reviewed by t he EMA in 2013,
m ore t han 90% originat ed from EudraVigilance. Det ails of signal det ect ion act ivit ies are present ed in
Annex V and progress in t erm s of signal m anagem ent in t he EU is described in Annex VI . Addit ionally,
EMA prepares dat a out put report s ( elect ronic react ion m onit oring report s, e- RMRs) t o support
m onit oring of dat a by NCAs in cont ext of t he work- sharing of m onit oring EV dat a. Over 19,000 of t hese
e- RMRs were generat ed and dist ribut ed t o NCAs and EMA st aff in 2013.
I n 2013, t he PRAC priorit ised and assessed 100 signals, t ot alling 130 signal discussions. This includes
43 signals det ect ed and validat ed by t he EMA and 57 det ect ed and validat ed by Mem ber St at es.
Am ong t he signals raised by t he EMA, t he evaluat ion of 21 signals result ed in changes of t he product
inform at ion ( including t he dist ribut ion of a Direct Healt hcare Professional Com m unicat ion in four cases
in order t o highlight im port ant new inform at ion t o prescribers) . The evaluat ion of 14 signals is
current ly at t he st age of an assessm ent of dat a provided by MAHs and t he evaluat ion of 7 signals was
concluded following t he assessm ent of available dat a wit h no furt her regulat ory act ion. For one signal,
a form al review of benefit - risk in t he scope of a refer ral under art icle 31 of Direct ive 2001/ 83/ EC was
init iat ed. Overall, t he evaluat ion of signals by t he PRAC has led t o t im ely conclusions of safet y reviews
and appropriat e act ions for t he prot ect ion of public healt h.
I n addit ion t o t he use of EudraVigilance for signal m anagem ent , furt her em phasis has been put on t he
support of pharm acovigilance referral procedures ( incl. urgent union procedures) by providing and
analysing safet y dat a for t he m edicinal product s concerned. I n 2013, t hese act ivit ies focused on
m edicinal product s cont aining t he act ive subst ances alm it rine, codeine, com bined cont racept ives,
cyprot erone/ et hinylest radiol, diacerin, dihydrocodeine, dom peridone, est radiol ( t opical use) , flupirt ine,
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
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nicot inic acid and derivat ives, st ront ium ranelat e, solut ions for infusion cont aining hydroxyet hyl st arch,
t et razepam , valproat e and relat ed subst ances, zolpidem .
To support t he assessm ent of PSURs by Mem ber St at es, EMA is also providing addit ional dat a analysis
report s from EudraVigilance and providing t raining t o assessors.
5 . Tr a n spa r en cy, com m u nica t ion an d t r a in ing
A key obj ect ive of t he new legislat ion is t o enhance t ransparency and opt im ise com m unicat ion in
pharm acovigilance. Following t he adopt ion of t he EudraVigilance Access Policy in 2011, t he EMA
launched in 2012 t he first phase of t he online access t o suspect ed adverse react ion report s 8 in all
official languages of t he EU on a new public websit e: ww w.adrreport s.eu. The launch highlight s t he
im port ance of adverse react ion report ing and EudraVigilance in safeguarding public healt h. The
inform at ion current ly published relat es t o over 700 m edicines and act ive subst ances aut horised
t hrough t he cent ralised procedure. I t is planned t o ext end t his websit e t o subst ances in nat ionally
aut horised m edicines subj ect t o worksharing for signal m anagem ent in 2014. The websit e, available in
all EU languages, was m aint ained t hroughout 2013 wit h 100% availabilit y.
Signals assessed by t he PRAC are publicly available in t he cont ext of t he publicat ion of t he PRAC
m eet ing agendas and m inut es 9 . I n Sept em ber 2013, t he Agency st art ed publishing t he adopt ed PRAC
recom m endat ions 10 on signals, in order t o facilit at e t heir im plem ent at ion by t he MAHs ( e.g. changes t o
t he product inform at ion) and t o increase t ransparency.
The Agency published t he list of m edicinal product s subj ect t o addit ional m onit oring 11 in April 2013 and
has m aint ained t he list prospect ively via m ont hly updat es. Medicines under addit ional m onit oring have
a black invert ed t riangle displayed in t heir package leaflet and sum m ary of product charact erist ics,
urging healt hcare professionals and pat ient s t o report any suspect ed adverse react ions via nat ional
report ing syst em s.
EMA also responds t o request s for EudraVigilance dat a in line wit h t he EudraVigilance Access Policy and
EU legislat ion on access t o docum ent s 12 , and in com pliance wit h EU personal dat a prot ect ion 13 . Det ails
on request s handled in 2013 are provided in Annex VI I .
I n 2013 t he EMA organised four I nform at ion Days for ext ernal st akeholders from m edicines regulat ory
aut horit ies and pharm aceut ical indust ry in relat ion t o EudraVigilance and t he new int ernat ional
st andards in pharm acovigilance.
Finally, t went y nine EudraVigilance and seven xEVMPD hands- on t raining courses were delivered t o
st akeholders in 2013 wit h 228 users following xEVMPD e- learning t raining. Addit ionally, EVDAS
( EudraVigilance Dat awarehouse Analysis Syst em ) t raining was held at t he Agency on t hree occasions,
t raining 44 expert s from 10 different NCAs.
8
ht t p: / / www .adrreport s.eu/ EN/ index.ht m l
ht t p: / / www .em a.europa.eu/ em a/ index.j sp?curl= pages/ about _us/ docum ent _list ing/ docum ent _list ing_000353.j sp&m id= WC
0b01ac05805a21cf
10
ht t p: / / www .em a.europa.eu/ em a/ index.j sp?curl= pages/ regulat ion/ docum ent _list ing/ docum ent _list ing_000375.j sp&m id=
WC0b01ac0580727d1c
11
ht t p: / / www .em a.europa.eu/ em a/ index.j sp?curl= pages/ regulat ion/ docum ent _list ing/ docum ent _list ing_000366.j sp&m id=
WC0b01ac058067c852
12
Regulat ion ( EC) No. 1049/ 2001 of t he European Parliam ent and of t he Council of 30 May 2001 regarding public
access t o European Parliam ent , Council and Com m ission docum ent s
13
Regulat ion ( EC) No. 45/ 2001 of t he European Parliam ent and of t he Council of 18 Decem ber 2000 on t he prot ect ion of
individuals wit h regard t o t he processing of personal dat a by t he Com m unit y inst it ut ions and bodies and on t he free
m ovem ent of such dat a
9
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
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6 . Con clusion
EudraVigilance cont inues t o be t he cent ral pillar t o support pharm acovigilance act ivit ies and t herefore
cont ribut es t o t he prot ect ion of public healt h in t he EU. The ever increasing num ber of report s received
in EudraVigilance is used for safet y m onit oring of m edicines by t he EMA and t he Mem ber St at es,
decision m aking in signals, PSUR and referral procedures by t he Agency’s scient ific com m it t ees and is
support ed by t ools for t ransparency for t he public, healt hcare providers, academ ia and MAHs. I n 2013
t ransparency was st rengt hened by t he publicat ion of adopt ed PRAC recom m endat ions for signals and
by est ablishing t he List of m edicinal product s subj ect t o addit ional m onit oring.
Furt her work was carried out in 2013 t o im prove t he dat a qualit y in EudraVigilance and a furt her
increase was not ed in t he num ber of m edicinal product subm issions by t he MAHs, est ablishing t he
m ost com plet e resource of aut horised m edicinal product s in t he EU.
Following t he Managem ent Board endorsem ent of t he funct ional specificat ions for t he EudraVigilance
dat abase ( “ EudraVigilance funct ionalit ies t o be audit ed” ) , t he Agency will cont inue t o work wit h t he
Mem ber St at es in 2014 t o furt her define and develop enhanced funct ionalit ies for t he benefit of t he
st akeholders and st ronger prot ect ion of public healt h.
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An ne x I - Su m m a ry of Eu dr a Vigilan ce r ela t e d a ct ivit ie s
I m ple m e nt a t ion a ct ivit ie s
St a t u s
Operat ion and m aint enance of EudraVigilance by EMA in collaborat ion
Cont inued during 2013
wit h Mem ber St at es
[ Legal basis: Regulat ion ( EC) 726/ 2004, Art icle 24]
Dat a qualit y review and duplicat e m anagem ent of adverse react ion
Cont inued during 2013
report s in EudraVigilance
[ Legal basis: Regulat ion ( EC) 726/ 2004, Art icle 24( 3) ]
Collect ion of core dat a set for all m edicinal product s aut horised in t he
Cont inued during 2013
EU in EudraVigilance
[ Legal basis: Regulat ion ( EC) 726/ 2004 Art icle 57( 2) , second
subparagraph]
Operat ion of t he signal m anagem ent processes based on
Cont inued during 2013
EudraVigilance dat a, including t he m ont hly provision of e- RMRs t o
lead Mem ber St at e 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 I m plem ent ing Regulat ion ( EU) 520/ 212, Art icle
21]
Access t o adverse react ion dat a held in EudraVigilance for CAPs
Cont inued during 2013
ht t p: / / www.adrreport s.eu/
[ Legal basis: Regulat ion ( EC) 726/ 2004, Art icle 24]
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An ne x I I – Eudra Vigilan ce da t a - pr ocessin g n e t w or k a nd
num be r of su spe ct e d a dve rse re a ct ion re por t s pr ocesse d by
t h e Eudr a Vigilan ce da t a ba se
Eu dr a Vigila n ce da t a - pr oce ssin g n et w or k ( Eu dr a Vigila n ce Ga t e w a y)
The EudraVigilance dat a- processing net work as referred t o in Art icle 24 of Regulat ion ( EC) No.
726/ 2004 facilit at es t he elect ronic exchange of adverse react ion report s bet ween t he EMA, m edicines
regulat ory aut horit ies and MAHs for all m edicines aut horised in t he European Econom ic Area ( EEA) .
This net work, know n as t he EudraVigilance gat eway, has been in cont inuous operat ion since Decem ber
2001.
During 2013, a t ot al of 15,747,644 t ransact ions were successfully perform ed by t he EudraVigilance
gat eway. Figure 1 present s t he t ot al num ber of t ransact ions perform ed per m ont h during 2013.
1,600,000
1,400,000
1,200,000
1,000,000
800,000
600,000
400,000
200,000
0
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Figur e 1 . Tot al num ber of t ransact ions perform ed per m ont h at t he level of t he EudraVigilance
Gat eway from 1 January 2013 – 31 Decem ber 2013
Eu dr a Vigila n ce da t a ba se
For m edicinal product s aut horised in t he EEA, adverse react ions report s are collect ed from bot h wit hin
and out side t he EEA.
The num bers present ed in figure 2 refer t o t he adverse react ion report s 14 received in t he post aut horisat ion m odule. During 2013, an average of 88,474 expedit ed adverse react ion report s were
received and processed per m ont h and subsequent ly m ade available for signal det ect ion and dat a
analysis by EMA and m edicines regulat ory aut horit ies in t he Mem ber St at es.
14
I n t he 2012 report , only "expedit ed" adverse react ion report s were present ed. Wit h t he new legislat ion, which has been
in force t hroughout 2013, alm ost all report s t ransm it t ed t o EudraVigilance are expedit ed, so t hese figures are for all
I CSRs/ cases t ransm it t ed t o EV.
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120,000
100,000
80,000
60,000
40,000
20,000
0
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Figur e 2 . Num ber of adverse react ion report s processed per m ont h in t he EudraVigilance dat abase
post - aut horisat ion m odule in 2013
Figure 3 present s t he t ot al num ber of adverse react ion report s 15 received in t he post - aut horisat ion
m odule grouped by EEA and non- EEA for 2013. Each individual case in EudraVigilance refers generally
t o a single pat ient ; an individual case is com posed of at least one report , called t he init ial report , which
m ight be com plem ent ed by follow- up report s wit h updat ed addit ional inform at ion on t he case.
1,200,000
1,000,000
800,000
750,916
600,000
485,471
400,000
200,000
370,185
256,900
0
I ndividual cases
Adverse react ion report s
EEA
Non- EEA
Figur e 3 . Num ber of individual cases/ adverse react ion report s processed bet ween Januar y and
Decem ber 2013 in t he Eudravigilance dat abase post - aut horisat ion m odule
15
I n t he 2012 report , only "expedit ed" adverse react ion report s and individual cases were present ed. Wit h t he new
legislat ion, which has been in force t hroughout 2013, alm ost all report s t ransm it t ed t o Eudravigilance are expedit ed, so
t hese figures are for all I CSRs/ cases t ransm it t ed t o EV.
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
Page 10/ 28
One very significant effect of t he new pharm acovigilance legislat ion was t o int roduce an obligat ion for
MAHs & NCAs t o inform t he Agency about adverse react ions report s received direct ly from pat ient s.
Wit hin t he EEA, t his has led t o t he num ber of such report s received in EudraVigilance each year
increasing significant ly ( and at a higher rat e t han t he increase in t he t ot al num ber of cases) since t he
ent ry int o force of t he new legislat ion ( 13,936 individual cases originat ing from consum ers were
t ransm it t ed t o EV in 2011, and 30,614 were t ransm it t ed t o EV in 2013) .
Figure 4 shows t he increase in t he num ber of EEA cases year- on- year and t he proport ionat ely great er
increase in t he num ber of direct pat ient report s, from 2011 ( t he last whole year before t he ent ry int o
force of t he new pharm acovigilance legislat ion) t o 2013. The num bers have been norm alised t o 2011
values ( t aking 2011 as 100) t o show t he com parat ive rat es of increase in direct pat ient report s versus
all report s. Table 1, im m ediat ely below Figure 4, gives bot h t he norm alised and t he t rue values.
Figur e 4 . The increase in t he rat e of direct pat ient report s com pared t o t he increase in t he rat e of all
report s from t he EEA following t he ent ry int o force of t he new PV legislat ion
D ir e ct pa t ie nt ca se s
Tot a l ca se s
250,000
35,000
30,000
200,000
25,000
150,000
20,000
15,000
100,000
10,000
50,000
5,000
0
0
2011
2012
2011
2013
2012
2013
Num ber of direct pat ient cases & t ot al cases t ransm it t ed t o EV each year from 2011 t o 2013
Ta ble 1 . The rat e of direct pat ient and t ot al EEA case report ing 2011- 2013
Year
Re por t e r
2011
2012
2013
N um be r of
% of 2 0 1 1
N um be r of
% of 2 0 1 1
N um be r of
% of 2 0 1 1
t ype
ca se s
rates
ca se s
rates
ca se s
rates
Pa t ie nt
13,936
100
20,115
144
30,614
220
163,275
100
186,136
114
234,546
144
Tot a l
16
True & norm alised values for EEA cases report ed t o EVPM year - on- year t aking 2011 as t he baseline for t he
norm alised values
16
These num bers do not t ake int o account t he de- duplicat ion w ork because t hey are concerned wit h t he increase in t he
rat e of report ing by prim ary sources and not t he rat e of t ransm ission of I CSRs t o EV by MAHs or NCAs, and t herefore t hey
are not direct ly com parable t o t he num bers present ed in figures 2 and 3.
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
Page 11/ 28
By 31 Decem ber 2013, t he EudraVigilance dat abase ( bot h post - aut horisat ion & clinical t rials m odules)
held a t ot al of 7,026,537 adverse react ion report s, referring t o 4,586,491 individual cases ( see figure
5) .
8,000,000
7,000,000
6,000,000
5,000,000
4,380,679
4,000,000
3,000,000
2,852,329
2,000,000
1,000,000
2,645,858
1,734,162
0
I ndividual cases
Adverse react ion report s
EEA
Non- EEA
Figur e 5 . Tot al num ber of individual cases/ adverse react ion report s received in t he EudraVigilance
dat abase from it s incept ion in Decem ber 2001 unt il 31 Decem ber 2013.
E- r e por t in g st a t us for M AH s a n d sponsor s of clin ica l t r ia ls
•
A t ot al of 758 MAHs ( at headquart er level) have sent report s t o t he EudraVigilance Post aut horisat ion Module ( EVPM) in t he period bet ween 1 Januar y 2002 and 31 Decem ber 2013.
•
A t ot al of 713 sponsors of clinical t rials ( at headquart er level) have sent report s t o t he
EudraVigilance Clinical Trials Module ( EVCTM) in t he period bet ween 1 May 2004 and 31 Decem ber
2013.
Tables 2 and 3 below show t he t ot al ( bot h expedit ed and non- expedit ed) num ber of unique cases and
I CSRs t ransm it t ed by MAHs and sponsors t o EVPM and EVCTM and t he 15- day r eport ing com pliance of
MAHs and sponsors of clinical t rials when report ing t o EVPM.
15- day report ing com pliance is calculat ed by subt ract ing t he dat e t he I CSR was received by t he
EudraVigilance Gat eway ( EV Message Gat eway Dat e) from t he dat e of receipt of t he m ost recent
inform at ion ( Receipt Dat e – I CH E2B( R2) A.1.7) . The receipt dat e is t reat ed as day 0, giving t he MAH
15 days following t hat day t o t ransm it t he report s.
For t he re- t ransm ission of report s originally t ransm it t ed t o MAHs by ot her organisat ions, t he receipt
dat e is t he dat e t he MAH r eceived t he m ost recent inform at ion from t he ot her organisat ion, not t he
dat e t hat t he ot her organisat ion received t he m ost recent inform at ion from t he original report er.
Nullificat ion and error report s are excluded from t he com pliance calculat ions. Only cases flagged by t he
MAHs as serious are included in t he calculat ions.
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
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Ta ble 2 . Num ber of I CSRs and unique cases t ransm it t ed by MAHs and sponsors t o EVPM and EVCTM
during 2013
EV Module
EVPM
EVCTM
Transm ission t ype
Num ber of t ransm issions
I CSRs
I ndividual Cases
I CSRs
I ndividual Cases
793,176
502,860
75,341
28,355
Ta ble 3 . Com bined 15- day report ing com pliance t o EVPM for all MAHs and sponsors in 2013.
Pe r ce n t a ge of I CSRs t r a n sm it t e d t o EVPM by M AH s/ Spon sor s w it h in 1 5 da ys:
96%
E- r e por t in g st a t us for N CAs
•
All 31 NCAs have been aut horised t o ent er int o product ion wit h EudraVigilance.
•
All NCAs have report ed I CSRs t o EVPM, except for AFLUV ( Liecht enst ein) and t he Division de la
Pharm acie et des Médicam ent s ( Luxem bourg) , for w hom special arrangem ent s are in place:
−
All I CSRs occurring in Liecht enst ein are t ransm it t ed t o EudraVigilance by MAHs.
−
The NCA for Luxem bourg has t heir report s t ransm it t ed by t he French nat ional agency.
Tables 4 & 5 below shows t he t ot al ( bot h expedit ed and non- expedit ed) num ber of unique cases and
I CSRs t ransm it t ed by NCAs t o EVPM and EVCTM and t he 15- day report ing com pliance of NCAs when
report ing serious cases t o EVPM.
15- day report ing com pliance is calculat ed by subt ract ing t he dat e t he I CSR was received by t he
EudraVigilance Gat eway ( EV Message Gat eway Dat e) from t he dat e of receipt of t he m ost recent
inform at ion ( Receipt Dat e – I CH E2B( R2) A.1.7) . The receipt dat e is t reat ed as day 0, giving t he MAH
15 days following t hat day t o t ransm it t he report s.
For t he re- t ransm ission of report s originally t ransm it t ed t o NCAs by MAHs, t he r eceipt dat e is t he dat e
t he NCA received t he m ost recent inform at ion from t he MAH, not t he dat e t hat t he MAH received t he
m ost recent inform at ion from t he original report er. Nullificat ion and error report s are excluded from
t he com pliance calculat ions. Only cases flagged by t he NCA as serious are included in t he calculat ions.
The overall NCA 15- day report ing com pliance was 89% , an increase from 2011 & 2012, when it was
84% .
Ta ble 4 . Num ber of I CSRs and unique cases t ransm it t ed by NCAs t o EVPM & EVCTM during 2013
EV Module
EVPM
EVCTM
Transm ission t ype
Num ber of t ransm issions
I CSRs
I ndividual Cases
I CSRs
I ndividual Cases
327,925
239,511
19,557
12,161
The figures for “ I ndividual Cases” in t he t able above include t he m ast er cases t ransm it t ed by t he EMA.
Ta ble 5 . Com bined 15- day report ing com pliance t o EVPM for all NCAs in 2013
Percent age of I CSRs t ransm it t ed t o EVPM by NCAs wit hin 15 days:
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
89%
Page 13/ 28
During 2013, t he following 10 NCAs t ransm it t ed SUSARs t o EVCTM ( SUSARs from ot her count ries were
received direct ly from sponsors of clinical t rials) :
M e m be r St a t e
N a t iona l Com pe t e nt Aut hor it y
BELGI UM
FEDERAL AGENCY FOR MEDI CI NES AND HEALTH
PRODUCTS
CZECH REPUBLI C
STATE I NSTI TUTE FOR DRUG CONTROL
DENMARK
DANI SH MEDI CI NES AGENCY
FI NLAND
FI NNI SH MEDI CI NES AGENCY
GERMANY
FEDERAL I NSTI TUTE FOR DRUGS AND MEDI CAL
DEVI CES
GERMANY
PAUL- EHRLI CH- I NSTI TUT
I TALY
AGENZI A I TALI ANA DEL FARMACO
NETHERLANDS
COLLEGE TER BEOORDELI NG VAN GENEESMI DDELEN
SWEDEN
MEDI CAL PRODUCTS AGENCY
UNI TED KI NGDOM
MEDI CI NES & HEALTHCARE PRODUCTS REGULATORY
AGENCY
Eu dr a Vigila n ce da t a ba se a n d su ppor t of sign a l m a n a ge m e n t pr ocess
A t ot al of 19,330 e- RMRs were generat ed in 2013 t o facilit at e t he cont inuous m onit oring of t he safet y
of m edicines by t he EMA and m edicines regulat ory aut horit ies in t he EEA.
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An ne x I I I - Tot a l num be r of m e dicin al pr odu ct su bm ission s
by M AH s
Tot a l num be r of m e dicina l pr oduct subm ission s by M AH s by 3 Fe b 2 0 1 4 1 7 in a ccor da nce w it h
Ar t icle 5 7 ( 2 ) , se con d su bpa r a gr a ph of Re gula t ion ( EC) 7 2 6 / 2 0 0 4
Tot al num ber of m edicinal product s ( count ed on t he basis of
459,290
EudraVigilance codes)
Tot al num ber of m arket ing aut horisat ion holders ( legal ent it ies)
3,996
est ablished in t he EU ( corresponding t o EudraVigilance codes)
The EudraVigilance code is t he level t o which a product is defined in t he cont ext of t he Art icle 57( 2) .
I t encom passes t he following param et ers:
•
Nam e of t he m edicinal product .
•
MAH.
•
Aut horising Com pet ent Aut horit y.
•
Count ry.
•
Act ive ingredient ( s) .
•
St rengt h( s) .
•
Pharm aceut ical form .
•
Aut horisat ion num ber.
•
Aut horisat ion procedure.
•
Pack size ( only if Com pet ent Aut horit y assigns unique m arket ing aut horisat ion num ber at package
level) .
17
Please not e t hat t his figure is as of 3 Feb 2014 and not 31 Dec 2013. This is due t o t echnical changes m ade t o t he
dat abase w hich m eans it is not possible t o give a precise figure as of 31 Decem ber 2013. The EMA est im at es t hat t he
num ber of MAHs and headquart ers w ould have been alm ost ident ical as of end- 2013 and t he num ber of m edicinal product s
w ould have been 10- 20,000 fewer
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
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An ne x I V - Eu dra Vigilan ce da t a qu alit y a ct ivit ies
I n accordance wit h Regulat ion ( EC) No 726/ 2004, Art icle 24( 3) , t he Agency operat es procedures t o
ensure t he qualit y and int egrit y of t he inform at ion collect ed in EudraVigilance. This includes ident ifying
duplicat e report s, perform ing t he coding of t he report ed m edicines and report ed act ive subst ances,
and providing feedback on t he qualit y of inform at ion sent by NCAs, MAHs and sponsors. The t able
below refers t o t he dat a qualit y act ivit ies perform ed by t he EMA in 2013.
Eudr a Vigila nce da t a qua lit y a ct ivit ie s in 2 0 1 3
I de nt ifying a nd m a na ging
Codin g of r e por t e d m e dicine s
Pr oviding fe e dba ck on da t a
duplica t e s
a nd a ct ive subst a n ce s
qua lit y
Num ber of duplicat e couples
Num ber of m edicinal
Tot al num ber of organisat ions
assessed: 122,308 ( in 2012 t his
product s/ act ive subst ances
subj ect t o dat a qualit y review:
was 96,298)
recoded: 87,660 ( I n 2012 t his
166 ( I n 2012 t his was 216)
was 82,076)
Num ber of ‘m ast er’ report s
Num ber of adverse react ion
generat ed based on duplicat ed
report s recoded: 555,798
dat a: 65,906 ( I n 2012 t his was
( referring t o 275,852 individual
83,393)
cases) .
I n 2012 616,001 adverse
react ion report s were recoded,
referring t o 356,000 individual
cases.
The overall rat e of duplicat es report ed t o EudraVigilance since it s launch is est im at ed at about 8% .
This includes “ different - sender” duplicat es as well as “ sam e- sender” duplicat es. “ Sam e- sender”
duplicat es are t hose were all duplicat es in t he clust er were t ransm it t ed t o EudraVigilance by t he sam e
organisat ion ( NCAs, MAHs, sponsors) .
I n accordance wit h Direct ive 2001/ 83/ EC, Art icles 107( 5) and 107a( 3) , t he Agency is collaborat ing
wit h MAHs and NCAs t o det ect and elim inat e duplicat e suspect adverse react ion report s. To t his end,
when suspect ed duplicat e suspect adverse react ion report s are det ect ed in EudraVigilance and bot h of
t he suspect ed duplicat es are from t he sam e sender, t he Agency will send inform at ion on t hese
suspect ed ‘sam e- sender’ duplicat es t o t he organisat ion which t ransm it t ed t hese cases t o
EudraVigilance and ask t hem t o m anage t hem appropriat ely.
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
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An ne x V – Signa l de t e ct ion
I n 2013, t he t ot al num ber of signals reviewed increased by approx. 11% com pared t o 2012. This
parallels t he increased num ber of I CSRs received in EudraVigilance, t he increasing use of st andardised
MedDRA queries ( SMQs) for analysis ( and subsequent ly a higher num ber of preferred t erm s which are
t racked) as well as t he im plem ent at ion of t he list of designat ed m edical event s ( DMEs) in t he e- RMR
and addit ional cat egories which warrant priorit y screening ( i.e. m ost relevant react ions t erm s/ DMEs,
fat al, paediat ric report s et c.) in 2012.
OVERVI EW
2013
2012
2011
2010
2009
2008
Tot al
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 pot ent ial signals originat ed from EudraVigilance, wit h ot her sources account ing for:
5% from t he scient ific lit erat ure, 3% from com m unicat ions received from ot her Regulat ory Agencies
worldwide ( 52 from MHLW/ PMDA, 15 from t he FDA, 5 from t he WHO and 4 from EMCDDA) and 1%
from ot her sources. The overview of signals validat ion by act ion t aken is provided below:
N um be r of signa ls
% of
N um be r of signa ls
% of
Ja n- D e c 2 0 1 3
t ot a l
Ja n- D e c 2 0 1 2
t ot a l
Closed
2126
87%
1869
84%
Ongoing
211
9%
195
9%
Monit ored
69
3%
97
4%
Priorit ised and analysed by PRAC
43
2%
52*
2%
Tot al
2449
100%
2213
100%
Act ion t a k e n
* reflect s t he num ber of signals com m unicat ed t o Rapport eurs by t he EMA in 2012 ( prior t o, and aft er
t he inaugurat ion of t he PRAC)
I n t ot al, 2,449 pot ent ial signals were reviewed in 2013 by t he Agency. 43 signals validat ed and
com m unicat ed t o t he Rapport eurs by t he Agency were priorit ised and analysed by t he PRAC during
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
Page 17/ 28
2013. Of not e, 2 of t hese signals had been under m onit oring by t he signal validat ion t eam at t he
Agency in 2012, 8 were pr om pt ed by t he scient ific lit erat ure and 5 by inform at ion received from ot her
regulat ory aut horit ies ( 3, 5 and 6, respect ively in 2012) .
At t he t im e of t his report , approxim at ely half of t he 43 signals handled by t he PRAC ( n= 21) led t o
recom m endat ion for changes t o t he product inform at ion, eit her direct ly ( n= 7) or following a
cum ulat ive review ( n= 14) , providing inform at ion t o pat ient s and healt hcare professionals on t he safe
use of t hese product s. For four signals, t his also included t he dist ribut ion of Direct Healt hcare
Professional Com m unicat ions ( DHPC) t o increase awareness about t he new safet y inform at ion. The
evaluat ion of 14 signals following t he recom m endat ion for a cum ulat ive review is current ly on- going.
The evaluat ion of seven signals was closed wit h no furt her regulat ory act ion required, wit h t he rout ine
pharm acovigilance act ivit ies deem ed sat isfact ory for furt her follow- up of t hese signals. One signal led
t o a form al evaluat ion of t he benefit - risk balance via an Art icle 31 referral.
Addit ionally, 69 signals ( approx. 3% ) were kept under m onit oring ( as of end of Dec 2013) . I f a signal
is m onit ored, in principle all new cases of t hat react ion sent t o EudraVigilance ar e reviewed.
Ove r vie w of sign a ls va lida t e d by t h e Age n cy pr ior it ise d a n d a ssesse d by t h e
PRAC
Since t he est ablishm ent of t he PRAC in July 2012, a new signal m anagem ent process has been in
place. Signals are com m unicat ed t o PRAC m em bers w ho confirm t he validit y of t he signals in line wit h
t he new legislat ion and t he Guideline on good pharm acovigilance pract ices: Module I X – Signal
m anagem ent . Confirm ed signals are t ransm it t ed t o t he PRAC for priorit isat ion and analysis. I n line wit h
t he new legislat ion’s aim of increasing t ransparency and com m unicat ion in pharm acovigilance, agendas
and m inut es of t he PRAC are being m ade public. Since Sept em ber 2013 t his also includes t he
recom m endat ions on signals as adopt ed by t he Com m it t ee, and can be found here.
An overview of validat ed signals is provided in t he following t ables, including t he lat est regulat ory
st at us as of 21 January 2014. When t he out com e of an init ial recom m endat ion is already known, bot h
are not ed sequent ially.
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
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Drug
I ssue
Lat est st at us or out com e
Adalim um ab
Derm at om yosit is
cum ulat ive review: updat e of
product inform at ion
Adalim um ab
I m m une Reconst it ut ion I nflam m at ory
cum ulat ive review
Syndrom e ( I RI S)
Aflibercept
Blindness
cum ulat ive review
Agent s act ing on t he renin-
Efficacy and safet y of dual blockade
Art icle 31 referral: evaluat ion
angiot ensin syst em
of t he renin- angiot ensin sy st em :
ongoing
m et a- analysis of random ised t rials
Agom elat ine
QT prolongat ion
cum ulat ive review: no
regulat ory act ion ( rout ine
pharm acovigilance)
Bevacizum ab
Anaphylact ic shock
cum ulat ive review: no
regulat ory act ion ( rout ine
pharm acovigilance)
Brent uxim ab Vedot in
Pulm onary t oxicit y
Capecit abine
Acut e renal failure
cum ulat ive review: updat e of
product inform at ion
cum ulat ive review: updat e of
product inform at ion
Capecit abine
Convulsion
cum ulat ive review
Cinacalcet
Fat al case wit h severe hypocalcem ia
updat e of product inform at ion
in a pediat ric clinical st udy
and DHPC
Clopidogrel
Acquired haem ophilia A
cum ulat ive review: updat e of
Clopidogrel
Cross- react ivit y bet ween clopidogrel
product inform at ion
updat e of product inform at ion
and t iclopidine am ong pat ient s wit h
previous allergic and/ or haem at ologic
react ions t o one of t hese product s
Clopidogrel
Eosinophilic pneum onia
cum ulat ive review: updat e of
product inform at ion
Denosum ab
Vasculit is
cum ulat ive review
Dexm edet om idine
I nfant ile apnoeic at t ack
cum ulat ive review
Docet axel
Serious and fat al drug int eract ions
cum ulat ive review: updat e of
involving CYP3A4 ( grapefruit j uice
product inform at ion
and dronedarone)
Docet axel
Throm bot ic m icroangiopat hy
cum ulat ive review: no
regulat ory act ion ( rout ine
pharm acovigilance)
Duloxet ine
I nt eract ion wit h aripiprazole -
cum ulat ive review: no
serot onin syndrom e
regulat ory act ion ( rout ine
pharm acovigilance)
2013 Annual Report on EudraVigilance for t he European Par liam ent , t he Council and t he Com m ission
EMA/ 145085/ 2014
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Drug
I ssue
Lat est st at us or out com e
Duloxet ine
I nt eract ion wit h linezolid leading t o
updat e of product inform at ion
serot onin syndrom e
Efavirenz; Em t ricit abine,
I nt eract ion wit h Ginkgo biloba
updat e of product inform at ion
Derm at om yosit is
cum ulat ive review: updat e of
efavirenz, t enofovir
Et anercept
product inform at ion
Exenat ide
I nj ect ion sit e abscess and cellult is
cum ulat ive review
Exenat ide, Liraglut ide
Cholecyst it is and cholelit hiasis
cum ulat ive review
Exenat ide, Liraglut ide
Gast roint est inal st enosis and
cum ulat ive review: updat e of
obst ruct ion
product inform at ion
Capillary leak syndrom e, cyt okine
cum ulat ive review: updat e of
release syndrom e
product inform at ion and DHPC
Heparin- induced t hrom bocyt openia
cum ulat ive review: no
Filgrast im , Pegfilgrast im
Fondaparinux
regulat ory act ion ( rout ine
pharm acovigilance)
Glycopyrronium
Angioedem a
cum ulat ive review
Hum an papillom avirus
Com plex regional pain syndrom e
cum ulat ive review
Com plex regional pain syndrom e
cum ulat ive review
I m m une Reconst it ut ion I nflam m at ory
cum ulat ive review
vaccine [ t ypes 16, 18]
( recom binant , adj uvant ed,
adsorbed)
Hum an papillom avirus
vaccine [ t ypes 6, 11, 16,
18] ( recom binant ,
adsorbed)
I nflixim ab
Syndrom e ( I RI S)
Leflunom ide
Drug React ion wit h Eosinophilia and
updat e of product inform at ion
Syst em ic Sym pt om s ( DRESS)
Leflunom ide
Myosit is
cum ulat ive review: no
regulat ory act ion ( rout ine
pharm acovigilance)
Lenograst im
Levet iracet am
( Syst em ic) capillary leak syndrom e
cum ulat ive review: updat e of
( CLS)
product inform at ion and DHPC
Hyponat raem ia and inappropriat e
cum ulat ive review: updat e of
ant idiuret ic horm one secret ion
product inform at ion
( SI ADH)
Mirabegron
Urinary ret ent ion
cum ulat ive review
Orlist at
Pharm acokinet ic drug int eract ion ( at
cum ulat ive review: updat e of
absorpt ion) wit h highly act ive
product inform at ion
ant iret roviral t herapy( HAART) leading
t o loss of HAART efficacy
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Drug
I ssue
Lat est st at us or out com e
Sit aglipt in,
Angioedem a due t o int eract ion
cum ulat ive review
Sit aglipt in/ m et form in
bet ween sit aglipt in and ACE inhibit ors
Som at ropin
Convulsions
cum ulat ive review: no
regulat ory act ion ( rout ine
pharm acovigilance)
Tem ozolom ide
Hepat ic failure
cum ulat ive review: updat e of
product inform at ion and DHPC
Teriparat ide
Anaphylact ic shock
updat e of product inform at ion
Thalidom ide
Post erior Reversible Encephalopat hy
cum ulat ive review: updat e of
Syndrom e ( PRES)
product inform at ion
Ticagrelor
Food int eract ion wit h grapefruit j uice
updat e of product inform at ion
Vem urafenib
Renal failure
cum ulat ive review
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An ne x VI - Signa l m an a gem en t in t h e EU
Signal m anagem ent is t he procedure which covers all t he st eps from t he det ect ion of a new signal t o
it s evaluat ion by t he appropriat e scient ific com m it t ee, including t he signal validat ion, signal
confirm at ion, signal analysis and priorit izat ion, signal assessm ent , recom m endat ion for act ion and t he
exchange of inform at ion bet ween t he relevant part ies.
Following t he experience from t he Pilot of signal m anagem ent in t he EU, furt her progress in signal
m anagem ent has been m ade t hrough t he Signal Managem ent Review Technical Working Group, a
collaborat ion group for cont inuous process im provem ent bet ween t he EMA and t he MSs in t he
European Medicines Regulat ory Net work. Three areas were ident ified for facilit at ion of signal
m anagem ent in t he EU: Signal m anagem ent t ools and processes, Met hodological guidance and Signal
det ect ion m et hods. The following act ions were com plet ed in 2013:
•
St andardised t em plat es for assessm ent of signal dat a and t he corresponding form for t he PRAC
recom m endat ion were developed for t he use by t he net work.
•
A Quest ions & answers on signal m anagem ent docum ent ( EMA/ 261758/ 2013) was published
on t he EMA websit e t o provide procedural guidance for MAHs regarding handling of signals
discussed at PRAC and any follow- up act ions t hat m ay arise.
•
The Agency st art ed publishing t he signal recom m endat ions adopt ed by t he PRAC on a
dedicat ed sect ion of t he EMA websit e 18 t o facilit at e im plem ent at ion of t he PRAC
recom m endat ions by t he MAHs and t o increase t ransparency.
•
The European Pharm acovigilance I ssues Tracking Tool dat abase was am ended following t he
im plem ent at ion of t he new pharm acovigilance legislat ion, t o accom m odat e t he new st eps in
signal m anagem ent process in line wit h t he new legislat ion and t o allow for a m ore com plet e
t racking of t he signal life cycle. The user guide was updat ed accordingly.
•
I nt egrat ion of signal procedures int o t he Agency’s t racking syst em s was achieved, t o allow for
t racking of signal procedures and t heir corresponding t im et ables. Furt her work for nat ionally
aut horised product s is foreseen in t he fut ure.
•
Furt her research int o st at ist ical signal det ect ion m et hods was carried out , wit h a view t o
updat e t he exist ing Guideline on t he use of st at ist ical signal det ect ion m et hods in EVDAS ( Doc.
Ref. EMEA/ 106464/ 2006) .
18
ht t p: / / www .em a.europa.eu/ em a/ index.j sp?curl= pages/ regulat ion/ docum ent _list ing/ docum ent _list ing_000375.j sp&m id=
WC0b01ac0580727d1c
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An ne x VI I - Re qu e st s for infor m a t ion an d docum en t s
Sevent y- t wo request s were answered in 2013, com pared t o 80 in 2012. Whereas t he t ot al num ber has
rem ained sim ilar, an increase was observed for request s from t he general public, HCPs, t he MAHs and
non- EU regulat ory aut horit ies. The drop in request s fr om j ournalist s was observed already in 2012 and
cont inued t hroughout 2013. This m ay be due t o t he proact ive publicat ion of adverse drug react ion dat a
for CAPs at ww w.adrreport s.eu, which st art ed on 31 May 2012. Dat a from seven request s were used t o
support t he decision m aking in t he cont ext of European referral procedures ( list ed below) .
The m edian response t im e in 2013 was 23 days ( range 0- 182 days) com pared t o 18 days in 2012
( range 0- 100 days) . The t im e of response is subj ect t o different fact ors such as t he urgency of t he
request , t he com plexit y of t he search needed and t he agreed t im eliness especially for int ernal EU
request s. 35% of t he request s were answered wit hin 14 days, 61% wit hin 1 m ont h and 86% wit hin
t wo m ont hs which is a decrease com pared wit h 2012 ( 49% , 68% and 95% , respect ively) and reflect s
t he increase in com plexit y of request s and num ber of product s/ react ions request ed.
An overview is provided below by t ype of request , aut horisat ion t ype of request ed product ( s) ,
request er t ype, t herapeut ic group of request ed product ( s) and origin count ry ( ext ernal request s only) .
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Ove r vie w of r e que st s h a ndle d in 2 0 1 3
Type of request er
Drug/ subst ance
I ssue
Type of request
I nt ernal EU
Acet ylsalicylic acid
ADRs for acet ylsalicylic acid in
Access t o inform at ion
Regulat ory Net work
low dose
and docum ent s
MAH
Agom elat ine
Angioedem a
Access t o docum ent s
Law firm
Alendronat e
Alendronat e - ONJ
Access t o inform at ion
Flut am ide
Flut am ide - Deat h
Om eprazole
Om eprazole - Hepat it is and
Rim onabant
Hepat ot oxicit y
Rim onabant - Depression,
m anic depression and m ent al
disorders
I nt ernal EU
Aliskiren
Regulat ory Net work
Dat a of use in paediat ric
Access t o inform at ion
populat ion
and docum ent s
PML
Access t o inform at ion
I CSRs subm it t ed wit hin t he
Access t o inform at ion
I nt ernal EU
All subst ances in t he
Regulat ory Net work
dat abase
General Public
Allopurinol
Non- EU Regulat ory
Andrographis
All I CSR subm it t ed t o t he
Aut horit ies
paniculat a ( Burm .f.)
dat abase
Skin SOC
Access t o inform at ion
Nees.
I nt ernal EU
Ant idiabet ic
Pancreat it is and pancreat ic
Regulat ory Net work
m edicines
cancer
Non- EU Regulat ory
Arcoxia - et oricoxib
- Fat al out com es
Access t o inform at ion
- Cardiac disorders
and docum ent s
Aut horit ies
Access t o inform at ion
- Cent ral nervous syst em
- Vascular disorders
Academ ia
I nt ernal EU
Ast hm a m edicat ions
All ADRs report ed in children
Access t o docum ent s
in children
subm it t ed from 2007 t o 2011
At osiban
Cont am inat ion issues
Access t o inform at ion
Avast in -
Anaphylact ic shock
Access t o docum ent s
Ocular use
Access t o inform at ion
Regulat ory Net work
MAH
bevacizum ab
I nt ernal EU
Avast in -
Regulat ory Net work
Bevacizum ab
I nt ernal EU
Azit hrom ycin
Fat al arrhyt hm ias
Access t o docum ent s
Bedaquiline
All ADRs report ed t o t he
Access t o inform at ion
Regulat ory Net work
Journalist
dat abase
I nt ernal EU
Benzyl Alcohol
Gasping syndrom e
Access t o inform at ion
I nt ernal EU
Biphasic insulin
Hom ogeneit y issue
Access t o inform at ion
Regulat ory Net work
aspart
Journalist
Cabazit axel
Medicat ion errors
Access t o inform at ion
Non- EU Regulat ory
Clopidogrel
Acquired haem ophilia A
Access t o docum ent s
Regulat ory Net work
Aut horit ies
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Type of request er
Drug/ subst ance
I ssue
Type of request
I nt ernal EU
Codeine
Dat a t o support t he Referral
Access t o inform at ion
Regulat ory Net work
General Public
procedure
Colchicine and
All I CSRs subm it t ed t o t he
Access t o inform at ion
m et hot rexat e
dat abase
I nt ernal EU
Com bined oral
Dat a t o support t he Referral
Regulat ory Net work
cont racept ives
procedure
I nt ernal EU
Cont racept ives
Em bolic and t hrom bot ic event s
Access t o docum ent s
Cyprot erone
Dat a t o support t he Referral
Access t o inform at ion
Access t o inform at ion
Regulat ory Net work
I nt ernal EU
Regulat ory Net work
I nt ernal EU
procedure
Dext rom et horphan
ADRs report ed in t he EU
Access t o inform at ion
Academ ia
Diabet ic m edicines
Research Prot ocol
Access t o inform at ion
I nt ernal EU
Diacerein
Dat a t o support t he Referral
Access t o inform at ion
Regulat ory Net work
Regulat ory Net work
MAH
procedure
Digoxin
Det ails of all t he I CSRs
Access t o docum ent s
Am it ript yline
subm it t ed
Academ ia
Dom peridone
All I CSRs subm it t ed t o t he
Access t o inform at ion
dat abase
and docum ent s
I nt ernal EU
Dom peridone
Dat a t o support t he Referral
Access t o inform at ion
Regulat ory Net work
Journalist
I nt ernal EU
procedure
Drospirenone
Efavirenz
Regulat ory Net work
All ADRs report ed t o t he
Access t o inform at ion
dat abase
and docum ent s
Cancer report s and birt h
Access t o inform at ion
defect s
General Public
Enoxaparin
Cardiovascular disorders
Access t o inform at ion
Journalist
Exenat ide
Cancer of t he t hyroid and
Access t o inform at ion
Liraglut ide
pancreat ic glands
Lixisenat ide
Sit aglipt in
Saxaglipt in
Linaglipt in
Vildaglipt in
I nt ernal EU
Fluenz and Fluariz
Medicat ion errors
Access t o inform at ion
Flupirt ine
Dat a t o support t he Referral
Access t o inform at ion
Regulat ory Net work
I nt ernal EU
Regulat ory Net work
European
procedure
Gardasil
Mult iple Sclerosis
Parliam ent
I nt ernal EU
Access t o inform at ion
and docum ent s
Gilenya - fingolim oid
PML
Access t o inform at ion
Gilenya - fingolim oid
PML
Access t o inform at ion
Havrix, Engerix and
Mult iple sclerosis
Regulat ory Net work
I nt ernal EU
Regulat ory Net work
General Public
and docum ent s
Access t o docum ent s
Twinrix
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Type of request er
Drug/ subst ance
I ssue
Type of request
I nt ernal EU
Heparins
Trend analysis of ADRs
Access t o inform at ion
Hexoprenaline
All I CSRs subm it t ed t o t he
Access t o inform at ion
dat abase
and docum ent s
Com plex regional pain
Access t o inform at ion
Regulat ory Net work
I nt ernal EU
Regulat ory Net work
Non- EU Regulat ory
HPV Vaccines
Aut horit ies
MAH
syndrom e
Hydroxyet hyl st arch
Tot al of I CSRs and cases
Access t o inform at ion
report s wit h fat al out com e
I nt ernal EU
I not uzum ab
Veno- occlusive disease and
Access t o inform at ion
Regulat ory Net work
ozogam icin
hepat ot oxicit y
and docum ent s
I nt ernal EU
I nt erferon bet a
Risk of collapsing focal
Access t o inform at ion
Regulat ory Net work
Non- EU Regulat ory
segm ent al glom erulosclerosis
I nt ralipid
Report s of ADRs subm it t ed for
Access t o inform at ion
an specific form ulat ion
and docum ent s
Lopinavir/ rit onavir
Drug int eract ion bet ween
Access t o docum ent s
and quet iapine
prot ease inhibit ors and
Aut horit ies
MAH
quet iapine
HCP
Magnesium sulfat e,
All ADRs report ed t o t he
Access t o inform at ion
t hiam ine and
dat abase
and docum ent s
procaine
MAH
Mirt azapine
Pancreat it is
Access t o docum ent s
Ot her EU Agencies
MMR Vaccines
I nform at ion on ADRs of MMR
Access t o inform at ion
vaccines in adult s.
Academ ia
Mult iple subst ances
Research prot ocol
Access t o inform at ion
General Public
Nat alizum ab
PML
Access t o docum ent s
I nt ernal EU
Nicot inic acid
Dat a t o support t he Referral
Access t o inform at ion
Regulat ory Net work
I nt ernal EU
procedure
Num et a G13% E
Regulat ory Net work
HCP
Hyperm agnesaem ia in pret erm
Access t o inform at ion
infant s
Paracet am ol
Allergic react ions
Access t o inform at ion
and docum ent s
Ot her EU Agencies
Phenibut
All I CSRs subm it t ed t o t he
Access t o inform at ion
dat abase
I nt ernal EU
Privigen
Haem olysis
Access t o inform at ion
Ranbaxy product s
Qualit y issues
Access t o inform at ion
Resorcinol
Endocrine, skin and
Access t o inform at ion
subcut aneous disorders
and docum ent s
Growt h ret ardat ion in children
Access t o docum ent s
Regulat ory Net work
I nt ernal EU
Regulat ory Net work
Consult ancy
MAH
Sert raline
and adolescent s
HCP
Sodium picosulphat e
Convulsions, seizures and
Access t o inform at ion
+ m agnesium cit rat e
epilepsy
and docum ent s
Polyet hylene glycol
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Type of request er
Drug/ subst ance
I ssue
Type of request
At ypical fem ur fract ure
Access t o inform at ion
( m acrogol) +
ascorbic
acid/ ascorbat e
Oral polyet hylene
glycol ( m acrogol)
MAH
St ront ium ranelat e
and docum ent s
I nt ernal EU
Synflorix
Regulat ory Net work
Non- EU Regulat ory
I nform at ion on case report s
Access t o inform at ion
from clinical t rials
Tacrolim us
Medicat ion errors
Access t o inform at ion
Thiocolchicoside
Genot oxicit y
Access t o inform at ion
I nt ernal EU
Tolcapone,
Tolcapone - Hepat ic disorders
Regulat ory Net work
nat alizum ab and
Nat alizum ab - PML
aloset ron
Aloset ron - Gast roint est inal
Aut horit ies
I nt ernal EU
Regulat ory Net work
and docum ent s
Access t o inform at ion
disorders
I nt ernal EU
Tredapt ive
Regulat ory Net work
( laropiprant , nicot inic
All ADRs report ed
Access t o inform at ion
acid)
Ot her EU Agencies
Tropicam ide
Misuse and abuse
Access t o inform at ion
HCP
Valproat e
Middle or/ and inner ear
Access t o inform at ion
Non- EU Regulat ory
Xaluprine -
Aut horit ies
m ercapt opurine
MAH
Yellox - brom fenac
m alform at ion
Medicat ion errors
Access t o I nform at ion
Cardiac failure
Access t o docum ent s
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