pharmacovigilance system in ukraine : history , results , objectives
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Pharmacovigilance system in Ukraine : history , results , objectives. Formation of pharmacovigilance in Ukraine. Formation of pharmacovigilance in Ukraine. 1996 – setting up the ADR Center of the State Pharmacological Center MoH Ukraine - PowerPoint PPT PresentationTRANSCRIPT
Pharmacovigilance system in Ukraine: history, results,
objectives
Formation of pharmacovigilance in Ukraine
1992… 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”
1993…
1994…
1995…
1996…
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 re-
registration 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 pharmacovigilancein 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
PharmacovigilanceDatabase
Department
Unit of ADR Reportsreceived
from Physicians
Pharmacovigilance Department
Regional Divisions ActivityOrganization and Coordination Unit
Unit for Analysis of ADR Cases
Recorded in Ukraine
Re-registration Materials Assessment Unit
Unit of ADR Reports received from Manufacturers
Regional Divisions Coordination Department
Monitoring Unit
Regional Divisions (n=27)
Regional Pharmacovigilance Divisions
Lugansk
Kyiv
Vinnytsa
Dnipropetrovsk
Poltava
Odesa
Kharkiv
Zaporizhzhia
Donetsk
Rivne
Lviv
Ivano-Frankivsk
Crimea
Chernivtsi
Chernigiv
SumyZhytomyr
SevastopolMykolaiv
Uzhgorod
Cherkasy
Kirovograd
Khmelnytskyi
Ternopil
Lutsk
Kherson
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 Inspectorate for Quality Control of Medicines
Quality control of medicines
State Expert Center
Pharmacovigilance
Detection of unsafe medicinal products
Regulatory decisionProposals submission to MoH Ukraine
Regulatory decisionProhibition, 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 informationin Ukraine
MoH
Ukraine
SECMoH Ukraine
Regional divisions
Oblast Health Care Administrations
Data collection, report - form № 69-healthy
Health care settingsData collection, report - form № 69-healthy
PhysicianForm 137/о, primary documentation
(case histories, hospital records)
ADR rep
orts
ADR spontaneous reporting by physicians in Ukraine
3246
4147
5283
7242 7347
670
41024190
6949
257298283
0
1000
2000
3000
4000
5000
6000
7000
8000
1996-1999
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
num
ber
of r
epor
ts
Number of ADR reports received/entered in the pharmacovigilance database (2007-2010)
5659
7115
8291
8673
734372426949
52835000
6000
7000
8000
9000
2007 2008 2009 2010
nu
mb
er o
f re
po
rts
entered received
Distribution of ADR among pharmaco-therapeutic classes (2010)
0
5
10
15
20
25
30
35
40
%
Antiinfectives for systemic use
Cardiovascular system
Nervous system
Alimentary tract and metabolism
Musculo-skeletal system
Blood and blood forming organs
Respiratory system
Antineoplastic and immunomodulating agents
Dermatologicals
Genito-urinary system and sex hormones
Sensory organs
Various
Systemic hormonal preparations
Antiparasitic products, insecticides and repellents
TOP-10 MP (2010)
INNNumber 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)
52,2
13,3
11,2
6,8
5
7,73,8Allergic reactions
GI
CNS
Cardiovascular
Organism as a whole (general)
Respiratory
Other
ADR distribution by method of MP administration, % (2010)
24,7 18,3 1,7
0,9
0,7
0,5
0,4
0,3
0,2
0,2
0,2
0,2
0,2
0,1
0,1
0,1
0,2
2,2
51,0
oral
i/v
i/m
local
s/c
block anesthesia
inhalation
eye drops
sublingual
rectal
vaginal
intranasal
infiltration anesthesia
instillation
parabulbar
subconjunctival
nasal
other methods
Development of ADR by duration of therapy (2010)
51,4
25
12,8
8,3
2,4
0,1
0 10 20 30 40 50 60
<=1
1,1-3
3,1-7
7,1-30
31-365
>356
du
rati
on
of
the
rap
y,
da
ys
%
ADR distribution by seriousness (2010)
79,5% – non-serious ADRs20,5% – 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)
Age, yrsAdults
AgeChildren
female male girls boys
19-30 9,3 5,1 0-27 days 0,04 0,1
31-45 12,4 7,728 days – 23
months 2,3 2,8
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
• 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
Number of registered ADR of MP for specified periodPatient exposure (number of patients having used product
for specified period)
ADRF = ×100%
Pharmacotherapy groups of MP during which use ADR were observed (2010)
0
5
10
15
20
25
30
35
40
%
Antiinfectives for systemic use
Cadiovascular system preparations
Nervous system preparations
Prepartions used for GI tract
Musculo-skeletal system preparations
Blood and blood forming preparations
Respiartory system preparations
Antineoplastic and immunomodulating preparations
Dermatological preprations
Genito urinary system preparation
Sensory organs preparations
Various
Systemic hormonal preparation
Antiparasitic preparations, insecticides and repellents
Prevalence of diseases according to ICD-10 per 100,000 population
0
10000
20000
30000
40000
50000
60000
70000
Prevalence of diseases according to ICD-10per 100,000 population
Diseases of the circulatory system
Diseases of the respiratory system
Diseases of the digestive system
Diseases of the musculoskeletal system
Diseases of genitourinary system
Diseases of eye
Endocrine diseases
Injury, poisoning
Diseases of the skin and subcutaneous tissue
Diseases of the nervous system
Mental disoders
Certain infectious and parasitic disorders
Diseases of the ear and mastoid process
Neoplasms
Prevalence of ADR among disease cases
Disease according to ICD-10Prevalence per
100,000 population
ADR per 100,000
population
Prevalence of ADR among cases
(1 ADR / disease cases)
Certain infectious and parasitic diseases 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
Endocrine, nutritional diseases 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
Medical errorswere observed in 2.7% of reports received in 2010. Amongthem 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 beendetected.
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
• 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
Cooperation in pharmacovigilance with MOH/manufacturers
• Each company has a qualified person responsible for pharmacovigilance
• Trainings in pharmacovigilance are regularly conducted for companies’ staff
• All MOH submit PSUR with re-registration materials
• 47 companies submit ADR reports
Submission of ADR reports
6949
519
13
7242
2070
78
7347
843
1120
1000
2000
3000
4000
5000
6000
7000
8000
num
ber of
rep
orts
2008 2009 2010
Spontaneous reportsCIOMS, worldСІОMS, Ukraine
During 2010 over 200 MP instructions for medical use were changed and updated based on results of expert evaluation of re-registration 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 Post-registration surveillance board
Central formulary committee
Regional formulary committeesMain physician
Monitoring in-patient departments for MP efficacy
and safety
Spontaneous reports
Clinical pharmacist (or
authorized person)
Pharmacotherapy committees of
health care settings
• 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
Cooperation of formulary system with pharmacovigilance
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
• 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
Further harmonization of pharmacovigilance in Ukraine according
to the amended European legislation
ADR with an established casual relationshipLethal, incl. expected SeriousUnexpected
ExpectedUnexpected Non-seriousExpected
MP manufacturers
Oder
Positive decision
Sales of MP
Patients PharmacistsPhysicians
State Inspectorateof medicines
Ministry of Health of Ukraine
Suspension or prohibition of registration
certificate validity
Development of medical and technical documents for medical
care (protocols, formularies)
Re-registration of medicinal product
Educational activity on safety and efficacy of
pharmacotherapy
Changes in MP instruction for medical
use
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 re-registration 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
2007-2008
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