EudraVigilance - Overview EudraVigilance to support EU Pharmacovigilance Activities ° EudraVigilance is the system to support EU pharmacovigilance activities ° It contains adverse reaction reports (Individual Case Safety Reports - ICSRs) for medicines licensed in the EU EU Regulatory Network ° Such reports are received from National Competent Authorities (NCAs), Challenges and Opportunities for Croatia marketing authorisation holders (MAHs) and Sponsors of clinical trials Important milestones: 5th Anniversary of the ALMP 13 – 14 November 2008 ° EudraVigilance Post-authorisation Module (EVPM) entered into production December 2001 Rijeka, Croatia ° EudraVigilance Clinical Trial Module (EVCTM) entered in production May 2004 ° Mandatory electronic reporting of ICSRs in the EEA as of 20 November 2005 Dr. Thomas Goedecke ° Release of the EudraVigilance Data Warehouse and Data Analysis System Scientific Administrator (EVDAS) to the EU NCAs on 2 July 2007 Pharmacovigilance and Risk Management ° Current number of reports (status 31 Aug. 08): 2.2 mill ICSRs EMEA

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What is the purpose of EudraVigilance? Data collected in EudraVigilance

° Support EU pharmacovigilance and risk management Post Authorisation Module (EVPM) activities: aim is the protection of public health ° Suspected serious adverse reactions ° Collection of suspected adverse reactions in the pre- and post- - Health care professionals’ spontaneous reporting authorisation phases - Post-authorisation studies (non-interventional) ° Monitoring of reporting compliance with expedited reporting - Worldwide scientific literature (spontaneous, non-interventional) requirements by NCAs and MAHs ° Suspected transmission via a medicinal product of an infectious agent ° Ad hoc evaluation of potential safety issues Applicable to all medicines authorised in the EEA independent of the authorisation procedure ° Monitoring of core risk profiles as outlined in EU Risk Management Plan (EU-RMP) Pre Authorisation Module (EVCTM) ° Support decision making process at the level of the Committee ° Suspected Unexpected Serious Adverse Reactions (SUSARs) reported for Human Medicinal Products (CHMP) and related working parties by sponsors of clinical trials - Interventional clinical trials Applicable to all investigational medicinal products for clinical trials authorised in the EEA

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Protection of Public Health Reporting Requirements EEA

Pharmacovigilance Information Source Suspected Serious Adverse Reactions occurring within the EEA • Safety Monitoring Interventional Clinical Trials • Signal Detection Spontaneous Reporting • Risk-Benefit Evaluation Post-Authorisation Safety Studies • Risk Management National 15 days EMEA Competent EudraVigilance Authority (& RMS) Post-Autorisation European where ADR occurred Sponsors of Commission Clinical Trials CT interventional European Database On Adverse Drug EMEA Reactions Health Care Professionals Marketing Worldwide Literature 15 days* 15 days* National Authorisation Post Autorisation Studies Post Competent Holders Internet* Authorities Patients* Solicitors*

General Health Care Marketing Authorisation Public Professionals * if medically confirmed Holder 5 / 19 6 / 19 Reporting Requirements non-EEA EU Risk Management Plans and EudraVigilance

Suspected Serious (Unexpected) Adverse Reactions occurring outside the EEA ° Electronic interface between EU-RMP and EudraVigilance ° Monitor identified and potential risks and important missing National information as outlined in the EU-RMP Safety Specification Competent Authority EMEA ° Integration of core risk profile in Reaction Monitoring Reports EudraVigilance generated in EudraVigilance to support pharmacovigilance activities for Post-Autorisation centrally authorised products Health Care Professionals Worldwide Literature ° Risk monitoring (identification and characterisation) Post Autorisation Studies Internet* ° Evaluation of the effectiveness of risk minimisation measures 15 days* Patients* ° The interface between EU-RMP and EudraVigilance is a living Solicitors* 15 days* document due at ° Submission of final version of EU-RMP at time of CHMP Opinion Marketing ° Each time the EU-RMP is updated in the future Authorisation * if medically confirmed Holder 7 / 19 8 / 19

EudraVigilance System - Functions EudraVigilance Data Processing

° Data processing network interlinking all National Competent ICSR Authorities in the EEA, the European Commission and the EMEA sponICtanSeoRus spontaneous EVPM to exchange information in pharmacovigilance t

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Unique repository of EU and non-EU adverse drug reactions U for development and authorised medicinal products ° Incorporates the international medical terminology AAMMPP IMIMPP EVMPD Medical Dictionary for Regulatory Activities (MedDRA) EU RMP

ICSR = Individual Case Safety Report AMP = Authorised Medicinal Product 9 / 19 IMP = Investigational Medicinal Product 10 / 19

General Aspects of Signal Detection EudraVigilance Reaction Monitoring Report

° Signal Detection describes a routine review of all ICSRs reported ° Reaction Monitoring Report is generated based on: to EudraVigilance: ° All spontaneously reported ICSRs over the last 15 or 30 days to EVPM ° For each product under monitoring all reactions reported within defined ° Generated at active substance level timeframes are listed for each System Organ Class ° All reports flagged as “suspect” and “interacting” by sender ° Reviewed by scientific staff at the EMEA in collaboration with Rapporteur/Co-Rapporteur ° List of reactions (MedDRA Preferred Terms) for each product at substance level, ranked by System Organ Class (SOC) indicating ° ‘Signals’ are based on statistical algorithms (e.g. Proportional ° New cases/fatal cases associated with reaction Reporting Ratio: an event is relatively more often reported for a ° Total number of cases medicinal product compared to the number of reports of this event for ° Origin (EU/non-EU) of cases all other medicinal products in the database) ° Proportional Reporting Ratio (PRR) and 95% Confidence Interval ° Each signal requires careful medical evaluation to be confirmed as ° Signals of Disproportionate Reporting (SDR) are highlighted in red if causally related with the product ° N ≥ 3 and ° Lower bound of 95% Confidence Interval of PRR ≥ 1

11 / 19 12 / 19 Interpretation of EudraVigilance Reaction Monitoring Report Signals of Disproportionate Reporting New cases (EU/non- EU/fatal) Statistical Signal ≠ Drug Safety Issue

Total cases (EU/non- ° No implication of causal relationship → each drug-event pair EU/fatal) requires medical evaluation based on case report details

PRR ° Artificial thresholds for Signals of Disproportionate Reporting (-/+ 95%CI) ° Nature and quality of data in database on which PRR is calculated needs to be considered → influence on PRR SDR ° Various sources of bias (e.g. underlying disease, statistical artefacts, etc.) ° Criteria for prioritisation (e.g. labelledness/listedness, impact on public health, change of frequency or seriousness, subgroup analysis etc.)

Guideline on the Use of Statistical Signal Detection Methods in the EudraVigilance Data Analysis System, 13 / 19 Doc. Ref. EMEA/106464/2006 rev. 1 14 / 19

Draft EudraVigilance Access Policy Example: Reactions per System Organ Class Number of Reactions reported for PRODUCT X According to Article 26, paragraph (3) and Article 57, paragraph (1)(d) (01 Jan 2002 - 31 Dec 2007)

2500 of Regulation (EC) 726/2004 2275

2000

Stakeholder Data access proposal 1466 1500

European Commission, National Online access to all data in 1021 1046 1000 851 877 891 Competent Authorities and the EVDAS 675 568 454 EMEA 500 370 366 392 309 287 292 221 210 205 182 162 174 164 174 121 Healthcare Professionals and Aggregated data to be published 13 0

General Public on the EudraVigilance website rs rs rs rs rs rs rs s rs rs s s ns rs s ) rs s rs rs rs rs rs es s rs e de e de de de e on de de ion on io e er ps e on de e e e e c re de rd or rd or or or rd iti or or at ti at rd rd ly ord iti or rd rd rd rd an du or iso is so is is is iso d is is st ica tig iso so po is nd is iso so so so st ce is d d di d d d l d on d d fe pl s d di d d o d d di di di m ro d m ac ic th ne ye a c ry m in m ve n e n m l c ric ry st al e cu p lar te di et rin ri E tin ite ilia te d co In itio su a te ta at na a in su cir al u ys ar en y oc es s b ys an l tr is sts ys na hi ri re st tis l ic sc s C g lab nd nt on to s s ra nu e t y s ri yc u b ia s cia ed a tic d d E oi ti pa ne on du d iv l c us pe s nd nd ed u o m V a an n tr tra e u cti ce n ct nc vo d P l a a m eo S d ph al r a as is H m fe ro a ne (i er an a m d an an Marketing Authorisation Holders to data m ili a G in Im In p ism n ed N en ste an ut al Restricted online access ly m E dm nd ol co ifi ium R y ic bc ic nd fa a a b d ec er e s c u rg a al, d g ta an p rp iv ra s u d it an nin Me al ns e ct tho nd S loo en rs o et u pu du , a B ng e is el nd , ro ry in and Sponsors of Clinical Trials in EVDAS sender based o rd po sk a cy p to Sk C iso y, lo nt an Re ira l d jur cu na gn sp ra In us lig re Re ne M ma P Ge n, nig be ms las op Ne 15 / 19 System Organ Class 16 / 19

Example: Number of reactions (PT level) per SOC Example: Number of reactions per age group Number of reactions reported at Preferred Term level per System Organ Class (SOC) for PRODUCT X (01 Jan 2002 - 31 Dec 2007)

SOC Reaction Preferred Term Total EEA Non EEA Blood and lymphatic system disorders Number of reactions per age group Aplastic anaemia 6 2 3 for PRODUCT X Autoimmune thrombocytopenia 3 2 1 Bone marrow failure 9 6 3 (01 Jan 2002 - 31 Dec 2007) Coagulopathy 90 20 70 Coombs negative haemolytic anaemia 1 0 1 0 Disseminated intravascular coagulation 52 12 40 2 Eosinophilia 28 14 14 Factor V inhibition 1 0 1 7 15 Factor VIII inhibition 1 1 0 Febrile neutropenia 4 1 3 Term newborn infants (0 -1m) Cardiac disorders 189 Infants and toddlers (2m - 2y) Acute myocardial infarction 6 0 6 Children (3 -11y) Angina pectoris 1 0 1 Adolescents (12 - 17y) Arrhythmia 19 5 14 Arteriosclerosis coronary artery 3 0 3 Adults (18 - 64y) Atrial fibrillation 22 2 20 Elderly (more than 65y) Atrioventricular block 5 2 3 Cardiac failure 14 11 3 280 Cardiotoxicity 10 0 10 Hypertensive heart disease 2 0 2 Myocardial fibrosis 1 0 1 Myocardial infarction 36 11 25 Myocardial ischaemia 2 1 1 Nodal arrhythmia 1 0 1 Congenital, familial and genetic disorders Cleft lip and palate 1 1 0 Congenital anomaly 2 1 1 Congenital aortic stenosis 1 0 1 Congenital eyelid malformation 1 1 0 Dysmorphism 3 2 1 Epidermolysis 1 1 0 Intestinal malrotation 1 0 1 17 / 19 18 / 19 Limb reduction defect 1 1 0 Acronyms AMP Authorised Medicinal Product CHMP Committee for Human Medicinal Products EEA European Economic Area EMEA European Medicines Agency EU-RMP EU Risk Management Plan EVCTM EudraVigilance Clinical Trial Module EVDAS EudraVigilance Data Warehouse and Analysis System EVMPD EudraVigilance Medicinal Product Dictionary EVPM EudraVigilance Post-Authorisation Module International Conference of Harmonisation of Technical Requirements for Registration of ICH Pharmaceuticals for Human Use ICSR Individual Case Safety Report IMP Investigational Medicinal Product MAH Marketing Authorisation Holder MedDRA Medical Dictionary for Regulatory Activities1 NCA National Competent Authority PT Preferred Term RMS Reference Member State SDR Signal of Disproportionate Reporting SOC System Organ Class SPC Summary of Product Characteristic SUSAR Suspected unexpected serious adverse reaction

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