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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

http://www.ema.europa.eu/ema/index.jsp?curl=pages/home/Home_Page.jsp&mid=

• 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

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/07/WC500108212.pdf

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,


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

http://www.adrreports.eu/

http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/document_listing/document_listing_000353.jsp&mid=WC0b01ac05805a21cf

http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/document_listing/document_listing_000353.jsp&mid=WC0b01ac05805a21cf

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000375.jsp&mid=WC0b01ac0580727d1c


http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000366.jsp&mid=WC0b01ac058067c852

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000366.jsp&mid=WC0b01ac058067c852

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.


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) ]


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]


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]


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]



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


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.


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%


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.


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.


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. 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.


http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129138.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129138.pdf


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


pharm acovigilance)

Brentuxim ab Vedot in Pulm onary toxicit y cum ulat ive review: update of


Capecitabine Acute renal failure cum ulat ive review: update of


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


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


Clopidogrel Eosinophilic pneum onia cum ulat ive review: update of


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


Docetaxel Throm bot ic m icroangiopathy cum ulat ive review: no


pharm acovigilance)

Duloxet ine I nteract ion with ar ipiprazole -

serotonin syndrom e

cum ulat ive review: no


pharm acovigilance)



Duloxet ine I nteract ion with linezolid leading to

serotonin syndrom e


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


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



Filgrast im , Pegfilgrast im Capillary leak syndrom e, cytokine

release syndrom e


product inform at ion and DHPC

Fondaparinux Heparin- induced throm bocytopenia cum ulat ive review: no


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)


Leflunom ide Myosit is cum ulat ive review: no


pharm acovigilance)

Lenograst im (System ic) capillary leak syndrom e

(CLS)



Levet iracetam Hyponat raem ia and inappropriate

ant idiuret ic horm one secret ion

(SIADH)



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





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


pharm acovigilance)

Tem ozolom ide Hepat ic failure cum ulat ive review: update of


Teriparat ide Anaphylact ic shock update of product inform at ion

Thalidom ide Posterior Reversible Encephalopathy

Syndrom e (PRES)



Ticagrelor Food interact ion with grapefruit j uice update of product inform at ion

Vem urafenib Renal failure cum ulat ive review


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) .


http://www.adrreports.eu/


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


I nternal EU

Regulatory Network

Aliskiren Data of use in paediat r ic

populat 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


Non-EU Regulatory

Authorit ies

Andrographis

paniculata (Burm .f.)

Nees.

All ICSR subm it ted to the

database


I nternal EU

Regulatory Network

Ant idiabet ic

m edicines

Pancreat it is and pancreat ic

cancer


Non-EU Regulatory

Authorit ies

Arcoxia - etor icoxib - Fatal outcom es

- Cardiac disorders

- Cent ral nervous system

- Vascular disorders


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


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



I nternal EU

Regulatory Network

Codeine Data to support the Referral

procedure


General Public Colchicine and

m ethot rexate

All ICSRs subm it ted to the

database


I nternal EU

Regulatory Network

Com bined oral

cont racept ives

Data to support the Referral

procedure


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


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


MAH Digoxin

Am it r iptyline

Details of all the ICSRs

subm it ted


Academ ia Dom peridone All ICSRs subm it ted to the

database


and docum ents

I nternal EU

Regulatory Network

Dom peridone Data to support the Referral

procedure


Journalist Drospirenone All ADRs reported to the

database


and docum ents

I nternal EU

Regulatory Network

Efavirenz Cancer reports and bir th

defects


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


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


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



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


and docum ents

Non-EU Regulatory

Authorit ies

HPV Vaccines Com plex regional pain

syndrom e


MAH Hydroxyethyl starch Total of ICSRs and cases

reports with fatal outcom e


I nternal EU

Regulatory Network

I notuzum ab

ozogam icin

Veno-occlusive disease and

hepatotoxicit y


and docum ents

I nternal EU

Regulatory Network

I nterferon beta Risk of collapsing focal

segm ental glom erulosclerosis


Non-EU Regulatory

Authorit ies

I nt ralipid Reports of ADRs subm it ted for

an specific form ulat ion


and docum ents

MAH Lopinavir/ r itonavir

and quet iapine

Drug interact ion between

protease inhibitors and

quet iapine


HCP Magnesium sulfate,

thiam ine and

procaine

All ADRs reported to the

database


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.


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


I nternal EU

Regulatory Network

Num eta G13% E Hyperm agnesaem ia in preterm

infants


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


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


and docum ents

MAH Sert raline Growth retardat ion in children

and adolescents


HCP Sodium picosulphate

+ m agnesium cit rate

Polyethylene glycol

Convulsions, seizures and

epilepsy


and docum ents



(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


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


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


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


Documents

I documenti di: quotidianosanità · 2018-06-01 · E-reporting status for MAHs and sponsors of clinical trials ..... 12 E-reporting status for NCAs ... Signal management in the EU