Pharmacovigilance system in
Ukraine: history, results,
objectives
Formation of pharmacovigilance in
Ukraine
1992…
1993…
1994…
1995…
1996…
Setting up Pharmacological and Pharmacopoeial
Committees,
State Inspectorate for Medicines Quality Control,
Elaboration of fundamentals for regulatory and
legal basis of the pharmaceutical sector and
public health, adoption of the Law of Ukraine “On
Medicines”
Formation of pharmacovigilance in Ukraine
• 1996 – setting up the ADR Center of the State Pharmacological Center
MoH Ukraine
• 1999 – setting up the Pharmacovigilance Department of the State
Pharmacological Center MoH Ukraine
• 1999 – setting up the National ADR Database
• 1999 – Ukraine became an associated member of the WHO
Collaborating Centre for International Drug Monitoring
• 2000 – Order MoH Ukraine № 347 “On Approval of Instructions for
surveillance over adverse reactions/effects of medicinal products”
(registered in the Ministry of Justice of Ukraine)
• 2001 – Order MoH Ukraine №51 “About Reporting Adverse Effects of
Medicinal Products” (report card and procedure for ADR reporting
approved) 2001 - №292 “About Improvement of Reporting Adverse
Effects of Medicinal Products” (form of state statistical reporting ADR
cases in health care settings and methodical recommendations on
completion and submission of ADR report form approved)
• 2001-2002 – workshops on pharmacovigilance in all regions of Ukraine,
cities of Kyiv and Sevastopol
Formation of pharmacovigilance in Ukraine
• 2002 – setting up 10 regional divisions on pharmacovigilance
• 2002 – Ukraine became a full member of the WHO Drug Monitoring
Program
• 2003 – translation and publication of THE RULES GOVERNING
MEDICINAL PRODUCTS IN THE EUROPEAN UNION, VOLUME 9 –
Pharmacovigilance Medicinal Products for Human and Veterinary
use),developed within ICH process and adopted in EC)
• 2003-2004 – 28 studies of drug safety profile conducted
• 2006 – update of the pharmacovigilance legislation. In 2007 the MoH
Ukraine Order №898 is approved (provided is legal framework for
pharmacovigilance performance by manufacturers, interactions
between partners in pharmacovigilance )
• 2007 – development and publication of “Medicines Safety” Guidelines
• 2007 – First scientific and practical conference “Medicines safety: From
development to medical use”
• 2007 – publication of guidelines «The principles of formation and
procedure for ADR reporting by manufacturer»
• 2007 – Workshop “Current status and prospects of registration and reregistration procedure in Ukraine”
• 2007 – launch of “Rational Pharmacotherapy” journal.
Formation of pharmacovigilance in Ukraine
•
•
•
•
•
•
•
•
•
•
•
2008 – setting up the Postregistration Surveillance and 27 regional
pharmacovigilance divisions as subdivisions of the State Pharmacological
Center MoH Ukraine
2009 – translation and publication of the European Guidelines on
Pharmacovigilance for Medicinal Products for Human Use (Volume 9а) as
a basis for national guidelines on pharmacovigilance
2009 – launching training course on pharmacovigilance for
pharmaceutical manufacturers
2009 – Second scientific and practical conference “Medicines safety: From
development to medical use”
2009 – publication of a manual on safe use of cardiotropic medicines
2009-2010 – pilot project on drug efficacy and safety performed in
hospitals of the Zhytomyr Oblast
2011 – elaboration of a model presentation on pharmacovigilance for
physician
2011 – launching training course “Pharmacovigilance: control of ADRs
and ARV product efficacy in HIV patients”
2011 – elaboration of lecture course and tests of the elective course
“Adverse Drug Reactions” for students of medical universities
2011 – guide on safe use of NSAIDs elaborated
2011 – creation of a page on the web-site of the State Expert Center where
information on changes in safety section of the instructions for medical
use is placed (http://www.pharma-center.kiev.ua/view/farmn)
International documents used for harmonization
of legal framework of the pharmacovigilance
system in Ukraine
• Directive 2001/83/EC on the Community code relating to
medicinal products for human use
• Council Regulation (EEC) No 2309/93 of 22.07.1993 laying
down Community procedures for the authorization and
supervision of medicinal products for human and veterinary
use and establishing a European Agency for the Evaluation
of Medicinal Products
• VOLUME 9A. Оf The Rules Governing Medicinal Products in
the European Union. Guidelines on Pharmacovigilance for
Medicinal Products for Human Use
Legislation on pharmacovigilance
in Ukraine
• Law of Ukraine “On Medicines” of 1996 as amended in 1998
• MoH Ukraine Orders:
27.12.2006 № 898 “On Approval of Procedure for Surveillance
over Adverse Reactions to Medicinal Products Permitted for
Medical Use” (harmonized with EC directives)
• 24.07.2009 № 531 “On Approval of Procedure for Monitoring
of Safety and Efficacy of Medicinal Products in Hospitals”
• 01.09.2009 № 654 “On Approval of Plan of Measures for
Improving Postregistration Surveillance over Safety and
Efficacy of Medicinal Products in Hospitals”
• 31.08.2010 № 736 “On measures for implementation of
Monitoring of Safety and Efficacy of Medicinal Products in
Hospitals”
Founders of pharmacovigilance system
in Ukraine
Volodymyr Maltsev
(1948-2008)
Olexii Viktorov
(1945-2011)
Who is responsible for
pharmacovigilance in Ukraine?
The State Expert Center MoH Ukraine shall be
responsible for conducting surveillance over
adverse reactions to medicinal products
permitted for medical use.
(MoH Ukraine Order of 27.12.2006 №898, item 1.3)
Current pharmacovigilance system in Ukraine
(MoH Order № 898 of 27.12.06)
Ministry of Health of Ukraine
State Expert Center (SEC)
Postregistration
Surveillance Board
Regional divisions of
Postregistration Surveillance
Board
    
Spontaneous reporting
Examples of regulatory approaches to medicines
circulation in different countries
Countries (РА)
Pharmacovigilance
Quality Control
ЕС (European
Commission)
EMA –CHMP –PhVWP
European Directorate for
the Quality of Medicines
(EDQM)
Sweden (MPA)
Evaluation and Regulatory
Administration –
Pharmacovidilance Division
Supervision and Scientific
Information –Drug
Inspectorate
Great Britain
(MHRA)
Vigilance and Risk
Management of Medicines
Division
Inspection,
Enforcement and
Standards Division
Germany
(BfArM)
Pharmacovigilance Division
Strategy and Planning –
Process Organization
Quality Assurance
Denmark
(DMA)
Consumer safety Division
Medicine Control Division
Ukraine (MoH)
State Expert Center MoH –
Postregistration Surveillance
Board
State Inspectorate for
Quality Control of
Medicines MoH Ukraine
Structure of Postregistration Surveillance
Board
Pharmacovigilance
Database
Department
Pharmacovigilance
Department
Regional Divisions
Coordination
Department
Unit of ADR Reports
received
from Physicians
Unit for Analysis
of ADR Cases
Recorded in Ukraine
Regional
Divisions Activity
Organization and
Coordination Unit
Unit of ADR Reports
received from
Manufacturers
Re-registration Materials
Assessment Unit
Monitoring Unit
Regional Divisions (n=27)
Regional Pharmacovigilance Divisions
Rivne
Lviv
Chernigiv
Lugansk
Zhytomyr
Sumy
Poltava
Vinnytsa
Cherkasy
Ternopil
Lutsk
Dnipropetrovsk
Khmelnytskyi
Kyiv
Ivano-Frankivsk
Uzhgorod
Zaporizhzhia
Kharkiv Donetsk
Chernivtsi
Odesa
Kirovograd
Kherson Crimea
Mykolaiv Sevastopol
Main activities of the pharmacological system in
Ukraine
• Health care information and methodological provision on drug
safety issues (including development and conduct of specialized
and general training programs, courses. For the last two years
nearly 28,459 persons took part in trainings)
• Collection and assessment drug safety and efficacy information
received from physicians, manufacturers, international
organizations
• Control of PH functioning in health care and drug manufacturers
• Expert assessment of re-registration materials relating to
pharmacovigilance
• Recommendations for marketing authorization holders to change
or add information in the summary of product characteristics or
package leaflets
• Proposals for MoH on prohibition, suspension or renewal of the
marketing authorization.
Ways of detection of unsafe medicinal
products
State Expert Center
State Inspectorate for Quality
Control of Medicines
Pharmacovigilance
Quality control of medicines
Detection of unsafe medicinal products
Proposals submission to
MoH Ukraine
Regulatory decision
Regulatory decision
Prohibition, suspension or renewal of a
marketing authorization
Main methods of collecting information
on drug safety in postregistration period
• Spontaneous reports of suspected ADRs
reports
• Pharmacoepidemiological studies
• ADR monitoring
Scheme of collecting ADR information
in Ukraine
MoH
Ukraine
SEC
MoH Ukraine
Regional divisions
Oblast Health Care Administrations
Data collection, report - form № 69-healthy
Health care settings
Data collection, report - form № 69-healthy
Physician
Form 137/о, primary documentation
(case histories, hospital records)
ADR spontaneous reporting by
physicians in Ukraine
8000
7242
7000
7347
6949
number of reports
6000
5283
5000
4190 4102
4147
4000
3246
3000
2000
1000
283 298
257
670
0
19961999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
Number of ADR reports received/entered in the
pharmacovigilance database (2007-2010)
9000
8673
8291
number of reports
8000
7115
7000
7242
7343
6949
6000
5659
entered
5283
5000
2007
2008
2009
received
2010
Distribution of ADR among pharmacotherapeutic classes (2010)
Antiinfectives for systemic use
40
Cardiovascular system
35
30
Nervous system
Alimentary tract and metabolism
Musculo-skeletal system
25
% 20
Blood and blood forming organs
Respiratory system
Antineoplastic and immunomodulating agents
15
Dermatologicals
10
5
Genito-urinary system and sex hormones
Sensory organs
Various
0
Systemic hormonal preparations
Antiparasitic products, insecticides and repellents
TOP-10 MP (2010)
INN
Number of
ADR reports
Ceftriaxone
337
Amoxicillin and enzyme inhibitor
213
Diclofenac
177
Levofloxacin
168
Amoxicillin
144
Electrolytes in combination with other drugs
142
Lamivudine/Zidovudine
130
Enalapril
116
Ciprofloxacin
114
Pentoxifylline
112
Systemic ADR manifestations (2010)
Allergic reactions
3,8 7,7
GI
5
6,8
CNS
52,2
Cardiovascular
11,2
Organism as a whole (general)
13,3
Respiratory
Other
ADR distribution by method of MP
administration, % (2010)
oral
24,7
18,3
i/v
1,7
0,9
0,7
0,5
2,2
0,4
0,3
local
s/c
0,2
block anesthesia
0,2
inhalation
0,2
eye drops
0,2
51,0
i/m
sublingual
rectal
0,2
vaginal
0,1
intranasal
0,1
infiltration anesthesia
instillation
0,1
0,2
parabulbar
subconjunctival
nasal
other methods
duration of therapy, days
Development of ADR by duration of
therapy (2010)
>356
0,1
31-365
2,4
7,1-30
8,3
3,1-7
12,8
1,1-3
25
<=1
51,4
0
10
20
30
%
40
50
60
ADR distribution by seriousness
(2010)
79,5% – non-serious ADRs
20,5% – serious ADRs
•
•
•
•
•
7,3% involved patient hospitalization
5,2% involved temporary disability or incapacity
4,7% – life-threatening
3,9% – prolonged inpatient hospitalization
0,1% – resulted in death
ADR distribution by
gender and age, % (2010)
Adults
Age, yrs
19-30
Children
female
male
9,3
5,1
Age
girls
boys
0-27 days
0,04
0,1
2,3
2,8
31-45
12,4
7,7
28 days – 23
months
46-60
17,4
10,1
2-11 yrs
2,6
3,0
61-72
10,0
5,6
12-17 yrs
1,7
1,2
73-80
4,5
1,8
80+
1,6
0,9
Total
55,2
31,1
Total
6,6
7,0
•
•
•
At present 27% of health care settings
submit ADR reports
Annually all health care settings submit to
MoH the summary ADR reports
The pharmacovigilance database of the
State Expert Center MoH Ukraine includes
over 47,500 ADR reports
Criteria used for evaluation of MP
safety
• ADR frequency
• Ratio of unexpected and expected ADR, of
serious and non-serious ADR
• Prevalence of ADR among cases of diseases
• Signal detection and confirmation
• Risk/benefit ratio
ADR frequency
ADRF =
Number of registered ADR of MP for specified period
×100%
Patient exposure (number of patients having used product
for specified period)
•
Over 10% - very common ADR requiring obligatory MP
safety profile or immediate appropriate regulatory actions
•
1-10% - common ADR requiring either study of MP safety
profile or providing a risk management plan or introduction
of restrictions/precautions in instruction for medical use
•
0.1-1% - uncommon
•
0.01-0.1% - rare
•
Below 0.01% - very rare
Pharmacotherapy groups of MP during which
use ADR were observed (2010)
Antiinfectives for systemic use
40
Cadiovascular system preparations
Nervous system preparations
35
30
25
Prepartions used for GI tract
Musculo-skeletal system preparations
Blood and blood forming preparations
Respiartory system preparations
% 20
15
10
Antineoplastic and immunomodulating preparations
Dermatological preprations
Genito urinary system preparation
Sensory organs preparations
5
0
Various
Systemic hormonal preparation
Antiparasitic preparations, insecticides and repellents
Prevalence of diseases according to ICD-10
per 100,000 population
Diseases of the circulatory system
70000
Diseases of the respiratory system
60000
Diseases of the digestive system
Diseases of the musculoskeletal system
50000
Diseases of genitourinary system
40000
Diseases of eye
30000
Endocrine diseases
Injury, poisoning
20000
Diseases of the skin and subcutaneous tissue
10000
Diseases of the nervous system
Mental disoders
0
Prevalence of diseases according to ICD-10
per 100,000 population
Certain infectious and parasitic disorders
Diseases of the ear and mastoid process
Neoplasms
Prevalence of ADR among disease cases
Prevalence per
100,000 population
ADR per
100,000
population
Prevalence of ADR
among cases
(1 ADR / disease
cases)
3940,7
1,6
2466
Neoplasms
2159,4
0,5
4156
Mental disorders
4651,2
0,7
6406
Diseases of the musculoskeletal system
10098,9
1,2
8493
Diseases of the respiratory system
38438,6
4,3
8912
Diseases of the genitourinary system
10016,5
0,8
12287
Diseases of the nervous system
4898
0,4
13253
Diseases of the digestive system
17930,2
1,2
14547
Injury, poisoning
5142,8
0,3
16428
Diseases of the circulatory system
57211,9
3,0
19308
8365,1
0,4
20800
Diseases of the skin and subcutaneous
tissue
4990,2
0,2
23423
Diseases of the ear and mastoid process
3502,9
0,1
39301
Diseases of the eye and adnexa
9235,6
0,1
62476
Disease according to ICD-10
Certain infectious and parasitic diseases
Endocrine, nutritional diseases
Medical errors
were observed in
2.7% of reports
received in 2010.
Among
them in 10% of
cases the medical
error was the
reason of ADR.
As of 01.06.2011
the database
contains 710
reports where
medical errors
have been
detected.
Error
Use of MP regardless of contraindications:
%
56.7
– in children
67.5
– in pregnancy or lactation
15.8
– in diabetes mellitus
4.4
– in stomach ulcer
2.6
– in bronchial asthma
2.6
– in heart failure
1.8
– in trophic ulcers
0.9
– in abruption of placenta
0.9
– in epilepsy
0.9
– in hemorrhagic stroke
0.9
– in renal pathology
0.9
– in influenza-type condition
0.9
Overdose
25.9
Wrong route of administration
6.5
Neglect of allergy anamnesis
6.5
Off-label use
2.0
Error in mode of administration
1.0
Irrational concomitant use of MP with other medicines
0.5
Wrong dilution
0.5
Unidentified individual sensitivity
0.5
Steps for evaluating risk/benefit ratio
• Analysis of available reliable information about adverse
effects of MP
• Signal detection and confirmation
• Evaluation of alternative
• Regulatory decision
– Euphyllin with ethylene diamine, stabilizer
– Low molecular weight polyvinyl pyrrolidones
– Nimesulide- and paracetamol-containing combined MP of
resorptive action
– Rimonabant
– Efalizumab
– Sibutramine
– Rosiglitazone
Cooperation in pharmacovigilance with
MOH/manufacturers
• Conducting workshops and trainings (3 workshops, 12
trainings had been conducted within 2007-2010 );
• Conducting individual consultations (annually over 500);
• Issue of Guidelines on Principles of formation and
procedure of submitting ADR information by
MOH/manufacturer
• Cooperation in development of regulations, guidelines and
publications
• Publication of analytical and generalized materials in 23
periodicals
• Issue of Rational Pharmacotherapy Journal specialized in
pharmacovigilance
• Each company has a qualified person
responsible for pharmacovigilance
• Trainings in pharmacovigilance are
regularly conducted for companies’
staff
• All MOH submit PSUR with reregistration materials
• 47 companies submit ADR reports
Submission of ADR reports
8000
number of reports
7000
7347
7242
6949
6000
Spontaneous reports
CIOMS, world
СІОMS, Ukraine
5000
4000
3000
2000
1000
0
2070
519
78
13
2008
2009
843
112
2010
During 2010 over 200 MP instructions for
medical use were changed and updated
based on results of expert evaluation of reregistration materials according to the
current safety information and data
presented in PSUR.
Cooperation of formulary system with
pharmacovigilance
Ministry of Health of Ukraine
The State Expert Center
Post-registration surveillance board
Regional departments of Postregistration surveillance board
Monitoring in-patient
departments for MP efficacy
and safety
Spontaneous reports
Main physician
Clinical
pharmacist (or
authorized person)
Central formulary
committee
Regional formulary
committees
Pharmacotherapy
committees of
health care
settings
Cooperation of formulary system with
pharmacovigilance
• Participation with staff of RD, oblast physicians
in workshops on implementation of formulary
system
• Development of specific regulations on
involvement of oblast physicians in regional
formulary committees
Implementation of new methods of
collecting information on ADR
• Pilot project on “Monitoring of MP safety and
efficacy (Zhytomyr Oblast)” has been conducted
(2009-2010)
• Planning and monitoring MP efficacy and safety in
hospitals of health departments in 10 oblasts of
Ukraine (2010-2011)
• Conducting workshops for oblast physicians and
staff of RD on procedure for monitoring hospitals for
MP safety and efficacy
• Ukraine has participated in Russian translation of
WHO ADR classification (2011) and WHO
recommendations “A practical handbook on the
pharmacovigilance of antiretroviral medicines”
• Participation in international conferences conducted
under aegis of WHO
Further harmonization of
pharmacovigilance in Ukraine according
to the amended European legislation
• Participation in writing articles “State registration of MP” and
“Pharmacovigilance” of new wording of Law of Ukraine “On medicines”
• Translation and publication of VOLUME 9A of “The Rules Governing
Medicinal Products in the European Union” – Guidelines on
Pharmacovigilance for Medicinal Products for Human Use) (2010) being
the basic document for state guideline on pharmacovigilance
• Amendment of MoH Ukraine Order as of 27.12.2006 №898 related to:
– Involvement of nurses, pharmacists, consumers of MP (or their
representatives) to ADR reporting process
– Pharmacovigilance and risk management systems in MP
manufacturers
– Efficient cooperation of partners conducting pharmacovigilance
Ministry of Health of Ukraine
ADR with an established casual relationship
State Inspectorate Lethal, incl. expected
of medicines Unexpected
Expected
Unexpected
Expected
Suspension or
prohibition of
registration
certificate validity
Oder
Positive
decision
Serious
MP
manufacturers
Non-serious
Development of
medical and technical
documents for medical
care (protocols,
formularies)
Re-registration of
medicinal product
Changes in MP
instruction for medical
use
Educational activity on safety
and efficacy of
pharmacotherapy
Sales of MP
Patients
Physicians
Pharmacists
Practical contribution of Ukraine's
pharmacovigilance system in the process of safe
MP use (2009-2011)
The safety information about medicinal products with the
following active substances was updated through forming a
signal:
• Thiotriazolin
• Quercetin
• L-lysine aescinate
• Sodium chloride
• Dextran (glucose solution, rheopolyglucin)
• Ringer’s solution, Ringer’s lactate solution
• Tivortin
• Aflubin
In 2010 instructions for medical use of some infusion solutions
and blood substitutes were changed and updated according to
the current data on MP safety and expert evaluation of reregistration materials (the model instructions were developed)
Practical contribution of Ukraine's
pharmacovigilance system in the process of safe
MP use (2010)
•
•
According to the results of post-registration surveillance over 200 MP instructions for
medical use were changed and updated.
Based on sufficient information and an established casual relationship between ADR
and use of Glutargin (PC “Zdorovie”) and Eurespal (Servier) the “Adverse reactions”
section of instruction for medical use was updated:
– Glutargin: rarely pain in epigastria, nausea may be observed immediately after
use of medicinal product which are over on its own. In single cases allergic
reactions (urticaria, hyperimia, pruritus) may be observed
– Eurespal – changes have been introduced both in Ukraine and all countries
where this medicinal product is marketed:
• CVS disorders: rarely – moderate sinus tachycardia, which decreases when
dose reduced
• GI disorders : common – dyspepsia, nausea, pain in stomach; frequency
unknown – diarrhea, vomiting
• Nervous system disorders – rarely – somnolence; frequency unknown –
dizziness
• Skin and subcutaneous tissue disorders: rarely – erythema, fixed pigmentary
erythema, skin rash, urticaria, Quincke’s edema; frequency unknown –
pruritus
• General disorders: frequency unknown – asthenia (weakness), fatigue
The appropriate regulatory decisions on
medical use of some medicinal products in
Ukraine
Year
Name
Decision
1996
Phenacetin
Medical use is prohibited
1996
Cimetidine
Medical use is prohibited
1999
Hemodesis
Medical use is prohibited
2001
Phenylbutazone (butadion)
Medical use is restricted
2002
Gentamicin
Medical use is restricted
2003
Nitrofuran
(furacilin)
Medical use of oral tablets is
prohibited
2003
Nitrofurans
Medical use is restricted
2003
Kava-kava products
Medical use is prohibited
Year
Name
Decision
2003
Disintoxication solutions with low
molecular weigh polyvinylpyrolidone
Medical use is restricted
2005
Metamizole sodium (analgin)
Medical use is restricted
2005
Rofecoxib (rofica, denebol)
Medical use is restricted
2006
Thioridazine (sonapax, ridazin)
Medical use is restricted
2006
Euphylline
Medical use of pharmaceutical forms
with ethylenediamine, stabilizer is
prohibited
2007
Oseltamivir products (tamiflu)
Precautions of use are mentioned
20072008
Nimesulide products
Medical use is restricted
2009
Rimonabant (acomplia)
Medical use is prohibited
2009
Efalizumab (raptiva)
Medical use is prohibited
2009
Nimesulide and paracetamol
combined products for systemic use
Medical use is prohibited
2010
Sibutramine
Medical use is prohibited
2010
Rosiglitazone
Medical use is prohibited
Capabilities and main objectives of
pharmacovigilance system in Ukraine
• Detection of unsafe MP
• Detection of risk groups of pharmacotherapy
• Detection of typical medical errors being the reason for ADR
and working out measures for their minimization
• Education healthcare professionals, MP consumers about
safety issues of MP use
• Implementation of MP monitoring in hospitals as optimal
procedure for collecting information about ADR
• Involvement of nurses, pharmacists, consumers of MP in
ADR reporting
• Further harmonization of legislation on pharmacovigilance