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 registration procedure in Ukraine” » • 2007 – Workshop “Current status and prospects of registration and re • 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 a basis for national guidelines on pharmacovigilance 9а) as 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 Improving Postregistration Surveillance over Safety and Efficacy of Medicinal Products in Hospitals” • 31.08.2010 № 736 “On measures for implementation of Hospitals ” ” • 01.09.2009 № 654 “On Approval of Plan of Measures for Monitoring of Safety and Efficacy of Medicinal Products in

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 permitted for medical use.

medicinal products (

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)

Sweden

(MPA)

Great Britain

(MHRA)

Germany

(BfArM)

Denmark

(DMA)

Ukraine

(MoH) EMA –CHMP –PhVWP Evaluation and Regulatory Administration – Pharmacovidilance Division Vigilance and Risk Management of Medicines Division Pharmacovigilance Division Consumer safety Division State Expert Center MoH – Postregistration Surveillance Board European Directorate for the Quality of Medicines (EDQM) Supervision and Scientific Information –Drug Inspectorate Inspection, Enforcement and Standards Division Strategy and Planning Process Organization Quality Assurance – Medicine Control Division State Inspectorate for Quality Control of Medicines MoH Ukraine

Structure of Postregistration Surveillance Board

Pharmacovigilance Database Department Unit of ADR Reports received from Physicians Unit of ADR Reports received from Manufacturers Pharmacovigilance Department Unit for Analysis of ADR Cases Recorded in Ukraine Re-registration Materials Assessment Unit Regional Divisions (n=27) Regional Divisions Coordination Department Regional Divisions Activity Organization and Coordination Unit Monitoring Unit

Regional Pharmacovigilance Divisions

Rivne Zhytomyr Chernigiv Vinnytsa Sumy Cherkasy Lugansk Poltava Lviv Ternopil Lutsk Khmelnytskyi Kyiv Dnipropetrovsk Ivano-Frankivsk Uzhgorod Chernivtsi Zaporizhzhia Kharkiv Donetsk Kirovograd Odesa 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 7347

7000

6949

6000 5000

5283 4190 4102

4000

4147 3246

3000 2000 1000

283 298 257 670

0 1996 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Number of ADR reports received/entered in the pharmacovigilance database (2007-2010)

9000 8000 7000 6000 5000 7115 6949 5659 2007 5283 2008 8291 7242 entered 2009 8673 7343 received 2010

40 35 30 25 % 20 15 10 5 0

Distribution of ADR among pharmaco therapeutic classes (2010)

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)

INN

Ceftriaxone Amoxicillin and enzyme inhibitor Diclofenac Levofloxacin Amoxicillin Electrolytes in combination with other drugs Lamivudine/Zidovudine Enalapril Ciprofloxacin Pentoxifylline

Number of ADR reports

337 213 177 168 144 142 130 116 114 112

Systemic ADR manifestations (2010)

6,8 5 3,8 7,7 11,2 13,3 52,2 Allergic reactions GI CNS Cardiovascular Organism as a whole (general) Respiratory Other

24,7

ADR distribution by method of MP administration, % (2010)

51,0 18,3 1,7 0,9 0,7 0,5 2,2 0,4 0,3 0,2 0,2 0,2 0,2 0,2 0,1 0,1 0,1 0,2 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)

>356 31-365 7,1-30 3,1-7 1,1-3 <=1 0,1 2,4 8,3 12,8 0 10 20 25 30 % 40 50 51,4 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)

Age, yrs 19-30 31-45 46-60 61-72 73-80 80+ Total female Adults male

9,3 5,1 12,4 17,4 10,0 4,5 1,6 55,2 7,7 10,1 5,6 1,8 0,9 31,1

Age 0-27 days 28 days – 23 months 2-11 yrs 12-17 yrs Total girls Children boys

0,04 0,1 2,3 2,6 1,7 2,8 3,0 1,2 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 Patient exposure (number of patients having used product

×100%

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

40 35 30 25 % 20 15 10 5 0

Pharmacotherapy groups of MP during which use ADR were observed (2010)

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

70000 60000 50000 40000 30000 20000 10000 0 Prevalence of diseases according to ICD-10 per 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-10 Prevalence per 100,000 population

3940,7

ADR per 100,000 population

1,6

Prevalence of ADR among cases (1 ADR / disease cases)

2466 Certain infectious and parasitic diseases Neoplasms Mental disorders Diseases of the musculoskeletal system Diseases of the respiratory system Diseases of the genitourinary system Diseases of the nervous system Diseases of the digestive system Injury, poisoning Diseases of the circulatory system 2159,4 4651,2 10098,9 38438,6 10016,5 4898 17930,2 5142,8 57211,9 8365,1 0,5 0,7 1,2 4,3 0,8 0,4 1,2 0,3 3,0 0,4 4156 6406 8493 8912 12287 13253 14547 16428 19308 20800 Endocrine, nutritional diseases Diseases of the skin and subcutaneous tissue Diseases of the ear and mastoid process Diseases of the eye and adnexa 4990,2 3502,9 9235,6 0,2 0,1 0,1 23423 39301 62476

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

Use of MP regardless of contraindications: – in children – in pregnancy or lactation – in diabetes mellitus – in stomach ulcer – in bronchial asthma – in heart failure – in trophic ulcers – in abruption of placenta

Error the database contains 710 reports where medical errors have been detected.

– in epilepsy – in hemorrhagic stroke – in renal pathology – in influenza-type condition Overdose Wrong route of administration Neglect of allergy anamnesis Off-label use Error in mode of administration Irrational concomitant use of MP with other medicines Wrong dilution Unidentified individual sensitivity

%

56.7

67.5

15.8

4.4

2.6

2.6

1.8

0.9

0.9

0.9

0.9

0.9

0.9

25.9

6.5

6.5

2.0

1.0

0.5

0.5

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 re registration materials • 47 companies submit ADR reports

Submission of ADR reports

8000 7000 6000 5000 4000 3000 2000 1000 0 6949 519 13 2008 7242 2070 2009 78 7347 843 112 2010 Spontaneous reports CIOMS, world СІОMS, 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 Central formulary committee Regional departments of Post registration surveillance board Main physician Monitoring in-patient departments for MP efficacy and safety Spontaneous reports Clinical

pharmacist (or

authorized person)

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 Serious Non-serious Oder Positive decision

Suspension or prohibition of registration certificate validity Development of medical and technical documents for medical care (protocols, formularies) Educational activity on safety and efficacy of pharmacotherapy Re-registration of medicinal product Changes in MP instruction for medical use

Sales of MP MP manufacturers 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 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 – Glutargin: rarely “Zdorovie”) and Eurespal (Servier) the “Adverse reactions” section of instruction for medical use was updated:

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

1996 1996 1999 2001 2002 2003 2003 2003

Name

Phenacetin Cimetidine Hemodesis Phenylbutazone (butadion) Gentamicin Nitrofuran (furacilin) Nitrofurans Kava-kava products

Decision

Medical use is prohibited Medical use is prohibited Medical use is prohibited Medical use is restricted Medical use is restricted Medical use of oral tablets is prohibited Medical use is restricted Medical use is prohibited

Year Name Decision

2003 2005 2005 2006 2006 Disintoxication solutions with low molecular weigh polyvinylpyrolidone Metamizole sodium (analgin) Rofecoxib (rofica, denebol) Thioridazine (sonapax, ridazin) Euphylline 2007 2007 2008 2009 2009 2009 2010 2010 Oseltamivir products (tamiflu) Nimesulide products Rimonabant (acomplia) Efalizumab (raptiva) Nimesulide and paracetamol combined products for systemic use Sibutramine Rosiglitazone Medical use is restricted Medical use is restricted Medical use is restricted Medical use is restricted Medical use of pharmaceutical forms with ethylenediamine, stabilizer is prohibited Precautions of use are mentioned Medical use is restricted Medical use is prohibited Medical use is prohibited Medical use is prohibited Medical use is prohibited 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