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Drug Safety - Electronic Supplementary Material (ESM)
Patient reporting in the EU: Analysis of EudraVigilance data.
Banovac M1, Candore G1, Slattery J1, Houÿez F2, Haerry D3, Genov G1, Arlett P1
Corresponding author: Marin Banovac1
email: [email protected]
1 European Medicines Agency (EMA)
2 European Organisation for Rare Diseases (EURORDIS)
3 European Aids Treatment Group (EATG)
2
Member States
Figure 14. The ratio of Patient reports over HCP reports in EEA between July 2014 and June 2015. Patient reports are expressed as
Only Patient group, HCP reports are expressed as Only HCP.
4 Country abbreviations: AT – Austria; BE – Belgium; BG – Bulgaria; CY – Cyprus; CZ – Czech Republic; DE – Germany; DK –
Denmark; EE – Estonia; ES – Spain; FI – Finland; FR – France; GB – Great Britain; GR – Greece; HR – Croatia; HU – Hungary; IE –
Ireland; IS – Iceland; IT – Italy; LI - Liechtenstein; LT - Lithuania ; LU - Luxembourg; LV - Latvia; MT – Malta; NL – the
Netherlands; NO – Norway; PL – Poland; PT – Portugal; RO – Romania; SE – Sweden; SI – Slovenia; SK – Slovakia
3
Reactions
Only Patient Only HCP
MedDRA System Organ Class N
ICSR Percentage
N ICSR
Percentage
1 General disorders and administration site conditions
69,316 17.4% 330,164 13.0%
2 Nervous system disorders 49,731 12.5% 262,097 10.3%
3 Gastrointestinal disorders 36,754 9.2% 218,839 8.6%
4 Skin and subcutaneous tissue disorders
27,579 6.9% 223,136 8.8%
5 Psychiatric disorders 26,918 6.8% 116,241 4.6%
6 Musculoskeletal and connective tissue disorders
25,987 6.5% 97,274 3.8%
7 Investigations 19,796 5.0% 157,864 6.2%
8 Respiratory, thoracic and mediastinal disorders
19,094 4.8% 144,612 5.7%
9 Injury, poisoning and procedural complications
18,105 4.5% 131,001 5.1%
10 Infections and infestations 16,158 4.1% 116,520 4.6%
11 Cardiac disorders 14,061 3.5% 103,931 4.1%
12 Eye disorders 12,269 3.1% 47,925 1.9%
13 Vascular disorders 11,386 2.9% 102,992 4.0%
14 Metabolism and nutrition disorders 8,632 2.2% 71,630 2.8%
15 Reproductive system and breast disorders
6,316 1.6% 20,514 0.8%
16 Renal and urinary disorders 6,255 1.6% 63,180 2.5%
17 Immune system disorders 4,712 1.2% 57,599 2.3%
18 Blood and lymphatic system disorders
4,513 1.1% 114,159 4.5%
19 Ear and labyrinth disorders 4,482 1.1% 14,858 0.6%
20 Neoplasms benign, malignant and unspecified (incl cysts and polyps)
4,468 1.1% 43,567 1.7%
21 Hepatobiliary disorders 2,955 0.7% 47,192 1.9%
22 Pregnancy, puerperium and perinatal conditions
2,302 0.6% 23,128 0.9%
23 Surgical and medical procedures 2,260 0.6% 15,170 0.6%
24 Social circumstances 1,590 0.4% 4,919 0.2%
25 Endocrine disorders 1,404 0.4% 10,459 0.4%
26 Congenital, familial and genetic disorders
993 0.2% 10,312 0.4%
SUM 180,038 1,365,638
Table 1. System Organ Classes (SOCs) ranked by the most frequently reported in Only Patient group between July 2009 and July
2015.
4
SOC Only Patient
- Pre SOC
Only Patient - Post
SOC Only HCP -
Pre SOC
Only HCP - Post
Genrl 19.9% Genrl 16.2% Genrl 12.6% Genrl 13.3%
Nerv 12.5% Nerv 12.5% Nerv 10.7% Nerv 9.9%
Gastr 10.0% Gastr 8.8% Gastr 8.4% Skin 9.2%
Musc 6.7% Skin 7.1% Skin 8.2% Gastr 8.8%
Skin 6.6% Psych 7.1% Inv 6.6% Inv 5.8%
Psych 6.1% Musc 6.5% Resp 5.5% Resp 5.8%
Inv 5.5% Resp 5.0% Psych 5.0% Inj&P 5.4%
Resp 4.5% Inj&P 4.9% Inj&P 4.9% Infec 4.7%
Inj&P 3.9% Inv 4.7% Infec 4.4% Blood 4.7%
Infec 3.6% Infec 4.3% Card 4.3% Psych 4.1%
Eye 3.2% Card 3.7% Blood 4.2% Vasc 4.0%
Card 3.2% Eye 3.0% Vasc 4.1% Card 3.9%
Vasc 2.6% Vasc 3.0% Musc 3.9% Musc 3.7%
Metab 2.2% Metab 2.2% Metab 2.9% Metab 2.7%
Repro 1.3% Repro 1.7% Renal 2.4% Renal 2.6%
Renal 1.3% Renal 1.7% Immun 2.2% Immun 2.3%
Blood 1.2% Immun 1.3% Hepat 2.0% Eye 1.9%
Neopl 1.0% Ear 1.2% Eye 1.9% Neopl 1.7%
Immun 1.0% Neopl 1.2% Neopl 1.7% Hepat 1.7%
Ear 1.0% Blood 1.1% Preg 1.0% Repro 0.8%
Hepat 0.8% Hepat 0.7% Repro 0.8% Preg 0.8%
Preg 0.5% Preg 0.6% Surg 0.6% Surg 0.6%
Surg 0.5% Surg 0.6% Ear 0.6% Ear 0.6%
Cong 0.3% SocCi 0.5% Endo 0.5% Cong 0.4%
Endo 0.3% Endo 0.4% Cong 0.4% Endo 0.4%
SocCi 0.2% Cong 0.2% SocCi 0.2% SocCi 0.2%
Table 2. System Organ Classes (SOCs) ranked by most frequently reported by patients and HCPs before and after the
implementation of the new pharmacovigilance legislation.
5
Reaction MedDRA Preferred Term
Rank Only Patient
N ICSRs Rank
Only HCP N ICSRs
Headache 1 4,193 6 14,989
Nausea 2 4,094 2 22,397
Pyrexia 3 3,950 1 26,483
Fatigue 4 3,728 10 11,077
Dizziness 5 2,992 8 14,013
Drug ineffective 6 2,832 11 10,422
Diarrhoea 7 2,470 5 15,866
Vomiting 8 2,323 4 19,912
Injection site pain 9 2,262 18 3,825
Dyspnoea 10 2,119 3 20,801
Myalgia 11 2,074 14 7,756
Malaise 12 1,754 9 12,581
Injection site erythema 13 1,711 19 3,801
Hyperpyrexia 14 1,642 20 1,625
Pruritus 15 1,560 7 14,773
Pain in extremity 16 1,464 17 5,855
Arthralgia 17 1,384 16 6,336
Somnolence 18 1,320 12 9,800
Abdominal pain 19 1,230 13 9,143
Paraesthesia 20 1,224 15 7,432
Table 3. The most frequently reported PTs ranked by Only Patient in the pre-legislation period.
6
MedDRA Preferred Term
Rank Only Patient
N ICSRs Rank
Only HCP N ICSRs
Fatigue 1 7,953 17 11,076
Headache 2 7,881 11 14,993
Dizziness 3 6,225 15 11,295
Nausea 4 5,936 3 20,939
Pyrexia 5 5,116 1 28,631
Dyspnoea 6 4,510 2 22,111
Malaise 7 4,089 13 12,630
Palpitations 8 4,004 9 17,254
Diarrhoea 9 3,995 10 16,339
Myalgia 10 3,760 5 19,941
Vomiting 11 3,659 27 7,633
Drug ineffective 12 3,534 78 3,904
Arthralgia 13 3,224 33 6,834
Pruritus 14 3,080 6 18,322
Hyperhidrosis 15 2,850 39 6,467
Product quality issue 16 2,848 7 18,245
Pain 17 2,826 16 11,252
Rash 18 2,792 46 5,520
Asthenia 19 2,730 50 5,368
Insomnia 20 2,707 105 3,243
Table 4. The most frequently reported PTs by the Only Patient and the Only HCP categories in the post-legislation period. Rank
denotes the ranking of PTs for respective categories in the post-legislation period.
7
Fatal cases by primary source
Table 5. Absolute number of ICSRs by outcome according to the primary source(s).
Jul09 - Jul10
Jul10 - Jul11
Jul11 - Jul12
Total Pre
Jul12 - Jul13
Jul13 - Jul14
Jul14 - Jul15
Total Post
Only Patient Fatal 2% 3% 3% 3% 5% 4% 3% 4%
Only HCP Fatal 6% 7% 7% 6% 6% 6% 6% 6%
Table 6. Percentage of ICSRs by fatal outcome according to the primary source(s).
Jul09 -
Jul10
Jul10 -
Jul11
Jul11 -
Jul12
Total
Pre
Jul12 -
Jul13
Jul13 -
Jul14
Jul14 -
Jul15
Total
Post
Non fatal 26,373 16,709 21,066 64,148 31,710 34,063 43,746 109,519
Fatal 633 549 555 1,737 1,582 1,579 1,473 4,634
Non fatal 243,250 183,419 183,977 610,646 212,711 228,063 227,557 668,331
Fatal 16,103 13,053 13,014 42,170 14,584 15,618 14,289 44,491Only HCP
Only Patient
8
Substances
Figure 2. Top 20 reported active substances and vaccines in Only Patient group ranked by proportion of reports before
implementation of the new pharmacovigilance legislation.
Figure 3. Top 20 reported active substances and vaccines in Only Patient group ranked by proportion of reports after (red bars)
implementation of the new pharmacovigilance legislation.
10.7%
9.7%
2.9%
2.0%
2.0%
1.3%
1.3%
1.3%
1.0%
1.0%
0.9%
0.9%
0.9%
0.9%
0.8%
0.8%
0.8%
0.7%
0.7%
0.7%
0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0%
(h1n1)v-like virus
etanercept
pregabalin
varenicline
insulin aspart
sildenafil
strontium ranelate
ranibizumab
pneumococc. polysacch.
insulin detemir
adalimumab
levonorgestrel
liraglutide
pramipexole
interferon beta-1b
benfluorex
citalopram
dabigatran
lorazepam
agomelatine
Only Patient - Pre
3.6%
3.4%
1.7%
1.5%
1.3%
1.1%
1.1%
1.1%
1.1%
1.0%
0.9%
0.8%
0.8%
0.8%
0.7%
0.7%
0.7%
0.7%
0.7%
0.6%
0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% 3.5% 4.0%
etanercept
levothyroxine
pneumococc. polysacch.
adalimumab
di-te-per, hep b, polio, haemb
rivaroxaban
levonorgestrel
mmr
interferon beta-1a
di-te-per, hep b, polio
teriparatide
hpv
carbidopa, levodopa
amoxicillin, clavulanic acid
(h1n1)v-like virus
methotrexate
cyproterone, ethinylestradiol
diclofenac
paracetamol
amoxicillin
Only Patient - Post
9
Figure 4. Top 20 reported active substances and vaccines in Only HCP group ranked by proportion of reports before implementation
of the new pharmacovigilance legislation.
Figure 5. Top 20 reported active substances and vaccines in Only HCP group ranked by proportion of reports after implementation of
the new pharmacovigilance legislation. (mmr = measles, mumps and rubella vaccine)
2.0%
1.6%
1.4%
1.2%
1.1%
1.0%
0.9%
0.9%
0.9%
0.8%
0.7%
0.7%
0.7%
0.6%
0.6%
0.6%
0.6%
0.6%
0.6%
0.6%
0.00% 0.50% 1.00% 1.50% 2.00% 2.50%
clozapine
(h1n1)v-like virus
pneumococc. polysacch.
etanercept
adalimumab
acetylsalicylic acid
infliximab
risperidone
varenicline
pregabalin
hpv
paracetamol
methotrexate
ibuprofen
di-te-per
diclofenac
dabigatran
zoledronic acid
di-te-per, pol. hemb
sunitinib
Only HCP - Pre
1.9%
1.7%
1.3%
1.2%
1.1%
1.0%
1.0%
1.0%
0.9%
0.8%
0.7%
0.7%
0.7%
0.7%
0.6%
0.6%
0.6%
0.6%
0.6%
0.5%
0.00% 0.50% 1.00% 1.50% 2.00% 2.50%
clozapine
rivaroxaban
acetylsalicylic acid
pneumococc. polysacch.
warfarin
dabigatran
amoxicillin, clavulanic acid
di-te-per, hep b, polio, haemb
adalimumab
mmr
methotrexate
ibuprofen
paracetamol
infliximab
rituximab
oxaliplatin
amoxicillin
ribavirin
bevacizumab
hpv
Only HCP - Post
10
Substance/Combination
Risk Ratio
Only Patient /
Only HCP
Only Patient
N ICSR
Only HCP
N ICSR
1 pre/pandemic influenza vaccine (h5n1) 87.0 306 31
2 estradiol, progesterone 74.0 151 18
3 humulus lupulus extract, passiflora extract, valerian extract
27.7 44 14
4 clotrimazole, hydrocortisone 22.4 122 48
5 liothyronine 21.9 119 48
6 calcium pantothenate 21.3 41 17
7 dimetindene maleate, phenylephrine 20.3 76 33
8 besilesomab 19.1 52 24
9 levothyroxine 16.3 5,438 2,937
10 lecithin 15.6 30 17
11 clobetasone 15.0 17 10
12 malathion 14.3 26 16
13 influenza vaccine (live attenuated, nasal) 14.2 199 124
14 medrogestone, estrogens conjugated 13.2 21 14
15 guaifenesin, paracetamol, phenylephrine 12.5 17 12
16 bifonazole 12.3 128 92
17 cetrimide, chlorhexidine gluconate 11.5 13 10
18 dextromethorphan hydrobromide, promethazine hydrochloride, paracetamol
11.2 14 11
19 teriparatide 10.0 1,474 1,304
20 cyanocobalamin, folic acid, pyridoxine 9.7 11 10
21 deanol bitartrate, thiamine nitrate, ginseng
9.7 11 10
22 clotrimazole 9.4 202 189
23 fish oil 9.2 25 24
24 minerals nos, vitamins nos 8.8 15 15
25 dimetindene, phenylephrine 8.8 12 12
26 cyproterone, ethinylestradiol 8.8 1,126 1,127
27 xylometazoline, ipratropium bromide 8.6 43 44
28 permethrin 8.5 25 26
29 clopamide, reserpine 8.4 20 21
30 cefodizime 8.3 16 17
31 polyethylene glycol 400 7.6 13 15
32 e.coli extract 7.6 19 22
33 xylometazoline 7.5 289 338
34 estradiol, levonorgestrel 7.5 70 82
35 escherichia coli, lyophilized 7.0 19 24
11
36 diphtheria, tetanus, pertussis (acellular, component) and hepatitis b (rdna) vaccine (adsorbed)
7.0 41 52
37 medrogestone 6.9 18 23
38 etanercept 6.9 13,518 17,329
39 pheneticillin 6.8 30 39
40 hydrocortisone acetate, polymyxin b sulfate, oxytetracycline
6.8 10 13
41
ascorbic acid, biotin, cyanocobalamin, folic acid, nicotinamide, riboflavin, thiamine nitrate, zinc, calcium, magnesium, pantothenic acid, pyridoxine hydrochloride
6.7 16 21
42
ascorbic acid, biotin, folic acid, nicotinic acid, riboflavin, thiamine, magnesium carbonate heavy, magnesium oxide, light, calcium carbonate, pantothenic acid, pyridoxine hydrochloride, zinc citrate trihydrate, vitamin b12
6.7 16 21
43 liothyronine sodium, levothyroxine sodium 6.6 30 40
44 estradiol, norethindrone 6.4 234 321
45 influenza virus 6.4 331 455
46 clodronic acid 6.3 205 285
47 glycerol 6.3 20 28
48 isopropyl alcohol 6.3 10 14
49 nicotine 5.9 741 1,111
50 ivacaftor 5.8 78 119
Table 7. Top 50 substances more likely to be reported by Only Patient according to RR where Only HCP was used as a reference. A
threshold of minimum 10 reports in EV was applied for both Only Patient and Only HCP groups.
12
Reported Indications
Figure 6. Reported indications on ICSRs for Only Patient category before and after the new legislation. Reported terms (indications)
were grouped according to SOCs.
Figure 7. Reported indications on ICSRs for Only HCP category before and after the new legislation. Reported terms (indications)
were grouped according to SOCs.
13
Figure 8. Top 20 reported indications in the Only Patient group ranked by relative risks compared to Only HCP for the 2009-2015
period. Reported terms (indications) were grouped according to HLTs.
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