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 Mo. H Ukraine • 1999 – setting up the Pharmacovigilance Department of the State Pharmacological Center Mo. H 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 Mo. H 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 Mo. H 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 Mo. H 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 Mo. H Ukraine 2009 – translation and publication of the European Guidelines on Pharmacovigilance for Medicinal Products for Human Use (Volume 9 а) 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 9 A. 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 • Mo. H 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 Mo. H Ukraine shall be responsible for conducting surveillance over adverse reactions to medicinal products permitted for medical use. (Mo. H Ukraine Order of 27. 12. 2006 № 898, item 1. 3)
Current pharmacovigilance system in Ukraine (Mo. H 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 –Ph. VWP 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 Inspection, of Medicines Division Enforcement and Standards Division Germany (Bf. Ar. M) Pharmacovigilance Division Strategy and Planning – Process Organization Quality Assurance Denmark (DMA) Consumer safety Division Medicine Control Division Ukraine (Mo. H) State Expert Center Mo. H – Postregistration Surveillance Board State Inspectorate for Quality Control of Medicines Mo. H 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 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 Mo. H 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 Mo. H Ukraine 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 Mo. H Ukraine SEC Regional divisions AD R re po rt s Mo. H Ukraine 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
Number of ADR reports received/entered in the pharmacovigilance database (2007 -2010)
Distribution of ADR among pharmacotherapeutic classes (2010)
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)
ADR distribution by method of MP administration, % (2010)
Development of ADR by duration of therapy (2010)
ADR distribution by seriousness (2010) q 79, 5% – non-serious ADRs q 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 Adults female 9, 3 5, 1 Age Children 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 Mo. H the summary ADR reports The pharmacovigilance database of the State Expert Center Mo. H 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 Number of registered ADR of MP for specified period ADRF = × 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)
Prevalence of diseases according to ICD-10 per 100, 000 population
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 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 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
Error Medical errors were observed in Use of MP regardless of contraindications: – in children 2. 7% of reports – in pregnancy or lactation received in 2010. – in diabetes mellitus Among them in 10% of – in stomach ulcer cases the medical – in bronchial asthma error was the – in heart failure reason of ADR. – in trophic ulcers As of 01. 06. 2011 – in abruption of placenta the database – in epilepsy contains 710 – in hemorrhagic stroke reports where medical errors have – in renal pathology – in influenza-type condition been detected. Overdose % 56. 7 67. 5 15. 8 4. 4 2. 6 1. 8 0. 9 0. 9 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
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 9 A 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 Mo. H 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) Educational activity on safety and efficacy of pharmacotherapy Re-registration of medicinal product Changes in MP instruction for medical use 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
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