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