1 2 3 25 May 2010 EMA/CVMP/PhVWP/471721/2006 Veterinary Medicines and Product Data Management 4 5 6 Recommendation for the basic surveillance of Eudravigilance Veterinary data Draft 7 Draft agreed by Pharmacovigilance Working Party 11 May 2010 Adoption by CVMP for release for consultation 19 May 2010 End of consultation (deadline for comments) 30 November 2010 8 Comments should be provided using this template. The completed comments form should be sent to vet-guidelines@ema.europa.eu; Fax +44 20 7418 8447 9 Keywords Adverse event, EudraVigilance Veterinary DataWarehouse, signal detection, surveillance 7 Westferry Circus Canary Wharf London E14 4HB United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8447 E-mail info@ema.europa.eu Website www.ema.europa.eu An agency of the European Union European Medicines Agency, 2010. Reproduction is authorised provided the source is acknowledged.
10 11 12 Recommendation for the basic surveillance of Eudravigilance Veterinary data Draft 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Table of contents 1. Introduction (background)... 3 2. Scope... 4 3. Legal basis... 4 4. Surveillance of data related to the use of centrally authorised products.5 4.1. Routine analysis of adverse event reports... 5 4.2. Methodology... 5 4.3. Time periods for routine assessment... 6 4.4. Intensive monitoring... 7 4.5. Monitoring of adverse events in humans having occurred in a third country... 7 5. Surveillance management procedures - roles and responsibilities in surveillance of centrally authorised products... 7 5.1. The rapporteur supported by pharmacovigilance expert(s) (PhV expert(s))... 8 5.2. The CVMP Pharmacovigilance Working Party (PhVWP-V)... 8 5.3. The Committee for Medicinal Products for Veterinary Use (CVMP)... 8 5.4. The Agency... 9 6. References and links to websites... 9 EMA/CVMP/PhVWP/471721/2006 Page 2/9
30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 Executive summary This recommendation includes guidance on the use of adverse event data related to veterinary medicinal products that are available in EudraVigilance Veterinary (EVVet), the European Union (EU) central database. The availability of adverse event data in a central EU database opens up a new dimension to the surveillance of veterinary medicinal products in the EU. The aim of the recommendation is to facilitate surveillance in a harmonised way with effective use of resources. The recommendation includes a risk based approach that foresees for most of the veterinary medicinal products in the EU to be monitored in accordance with a routine process while the possibility remains to perform intensive monitoring for a minority of veterinary medicinal products or active substances whenever considered necessary. The recommendation describes the processes and responsibilities for surveillance of veterinary medicinal products or active substances. A staged approach has been agreed for the implementation of the recommendation where the focus is first on veterinary medicinal products authorised via the centrally authorised procedure. The approach is foreseen to be expanded to all veterinary medicinal products in due course. It is envisaged to review the recommendation and accompanying standard operating procedure (SOP) within two years following their implementation in the light of experience gained to evaluate the proposed new process. 1. Introduction (background) As a joint effort between the European Commission, the European Union (EU) Member States and the European Medicines Agency (the Agency) a database called EudraVigilance Veterinary (EVVet) has been developed to contain spontaneous reports on adverse events related to veterinary medicinal products. Electronic reporting of adverse events became mandatory in November 2005 in the European Economic Area (EEA). EVVet provides a data-processing network and database management system for the exchange, processing and evaluation of adverse events. The EVVet data analysis system (otherwise known as EVVet DataWarehouse; DWH) has been developed for the analysis of the adverse events contained in EVVet. While surveillance of pharmacovigilance data of nationally authorised products had been limited to reports predominantly obtained at Member State level, the availability of a central database accessible for all regulators in the EU provides new opportunities for surveillance of adverse event data. Individual adverse event reports that have occurred within the EU are still first monitored at Member State level which enables a rapid intervention whenever necessary. As part of the EVVet system, adverse event reports are linked to the EVVet product database containing information on all veterinary medicinal products in the EU, in order to allow for analysis across products and active substances. While the EVVet product database contains information for all centrally authorised products, a fully validated EU central database containing all veterinary medicinal products authorised in the EU has yet to be made available. This is the main reason why the current recommendation is focused initially on adverse event data related to centrally authorised products, however, it is foreseen that the recommendation would, in due course, also be applied to all veterinary medicinal products in the EU. Predefined adverse event data analysis queries that are accessible in the EVVet DWH are the backbone of the surveillance procedure. These predefined queries based on filtering of data focus on the frequency of occurrence of specific VeDDRA 1 terms in adverse event reports. Certain statistical parameters (e.g. Proportional Reporting Ratio; PRR) are indicative of the relative occurrence of a VeDDRA term in relation to a specific product or active substance, however it still remains necessary to 1 Veterinary Dictionary for Drug Regulatory Activities EMA/CVMP/PhVWP/471721/2006 Page 3/9
74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 fully investigate the clinical relevance of all potential safety concerns (or so called signals) that may be detected. The current methodology is therefore based on the detection of events that are occurring at frequencies that are higher relative to the occurrence of such events for all other, or a group of, similar products in the database. The focus is to survey for events which were unknown for a particular product or active substance or which would be occurring at frequencies higher than expected. It should be highlighted that there remains considerable underreporting of adverse events related to veterinary medicinal products and that the EVVet system does not contain data related to the actual sales or use of a product which would allow for analysis on the basis of estimated exposure. It also needs to be noted that events considered non-serious are submitted on a voluntary basis. Therefore, a strategy for use and procedures for evaluation of data in EVVet are needed. This recommendation aims to provide a basis for practical harmonisation of the manner in which Member States evaluate data contained in EVVet thus facilitating the effective use of Member States resources. A risk based approach should allow for most of the veterinary medicinal products authorised in the EU to be monitored at routine established intervals with routine methods. However it would remain possible at all times to require more frequent or intensive monitoring for specific products or active substances. Decisions on placing products under intensive monitoring should be made following a risk based approach with consideration of, for example, the specific pharmacotoxicological and immunological knowledge available, known incidence and severity of adverse events or particular risks to humans related to the use of the products. 2. Scope This recommendation includes guidance on the use of adverse event data related to veterinary medicinal products that are available in EVVet, the EU central database. The aim is to provide a transparent methodology for the analysis of the data using the EVVet DWH to facilitate surveillance of all veterinary medicinal products in the EU taking into account the limited resources available. Detailed methodology is at present only provided for the surveillance of centrally authorised products, however, the principles would be applicable to all veterinary medicinal products, in due course. Regulatory steps which may be recommended following evaluation of adverse event data are described in Community legislation and related pharmacovigilance guidance (see References) and are not within the focus of this recommendation. Guidance related to access to the data contained in EVVet, in particular for the general public and the pharmaceutical industry, can be found in the EudraVigilance Access Policy for Medicines for Veterinary Use. This recommendation is intended to be used by regulators. 3. Legal basis Article 76 (1) of Directive 2001/82/EC states that the Agency in collaboration with Member States and the European Commission (EC) shall set up a data-processing network to facilitate the exchange of pharmacovigilance information regarding veterinary medicinal products marketed in the Community in order to allow the competent authorities to share the information at the same time. In accordance with Article 51 of Regulation (EC) 726/2004, the Agency in collaboration with Member States and the European Commission (EC) shall set up a data-processing network for the rapid transmission of data between the competent Community authorities in the event of an alert, relating to faulty manufacture, serious adverse reactions and other pharmacovigilance data regarding veterinary medicinal products authorised in the Community. EMA/CVMP/PhVWP/471721/2006 Page 4/9
117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 In accordance with Article 57(1) of Regulation (EC) 726/2004, the Agency, acting particularly through its Committees coordinates the supervision, under practical conditions of use, of medicinal products which have been authorised within the Community and the provision of advice on the measures necessary to ensure the safe and effective use of these products, in particular by evaluation, coordination of the implementation of pharmacovigilance obligations and the monitoring of such implementation. 4. Surveillance of data related to the use of centrally authorised products Surveillance of adverse event reports is taking place at different levels. At the initial reporting stage, the marketing authorisation holder as well as the national competent authority of the Member State where the event occurred will assess whether the report contains information that requires immediate investigation. Most often the information from one individual report will not need, or will be insufficient to require, immediate action and the report will follow the normal reporting route to EVVet. In cases where immediate action may be required (e.g. where new information emerges which might influence the evaluation of the benefits and risks of the veterinary medicinal product concerned) the company will inform the Agency, the Commission and the Member States directly on the matter. The competent authorities may consider taking urgent action in accordance with legislation or may initiate a rapid alert procedure. The principles of the methodology for assessment are risk based and ensure more frequent surveillance when products are initially placed on the market while extending the surveillance period in the later life cycle of a product. A certain observation in a few reports may require action for a specific product while the same observation in many reports would be considered normal for a different product. Although the analysis of the data may be guided by statistical parameters the end conclusions require in depth clinical judgment of the reports involved. 4.1. Routine analysis of adverse event reports Following the initial assessment of the individual reports by the marketing authorisation holder and the national competent authorities of the Member State for reports occurring within the EEA, all expedited reports, at least, are accumulated in EVVet. Adverse events, including human reports, occurring in a third country and eligible for expedited reporting are sent directly to EVVet and there is no initial assessment of the reports by any of the national competent authorities in the EU at the time of data transmission to EVVet. Although third country reports are subsequently evaluated by the rapporteur responsible for the centrally authorised product, it is considered necessary to ensure for initial screening by the Agency of third country reports in particular for human reactions, as described later. 4.2. Methodology Analysis of the data is predominantly based on the queries being developed in the EVVet DWH which includes all adverse event reports submitted to the central database up to previous day of the actual analysis. Data are transferred from EVVet to the DWH overnight. EMA/CVMP/PhVWP/471721/2006 Page 5/9
155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 The following strategy for analysis is recommended in the EVVet DWH: a. Query for an overview of the number of reports received for a particular product or active substance over the assessment period, categorised for EU reports and non-eu reports with information on the number of deaths in animals linked to the reports. b. Employ the specific query that allows for the comparison of the frequency and relative frequency (PRR) of the VeDDRA terms observed over a specific period compared to the frequency and relative frequency (PRR) for the same VeDDRA terms for all the data available for a particular product or active substance. This query also highlights the VeDDRA terms associated with the adverse reaction term(s) in Section 4.6 of the summary of product characteristics (SPC) and product literature for a specific product. The assessor is advised to focus on: Relative frequency of unexpected VeDDRA terms Changes or differences in the frequency of known VeDDRA terms Specific VeDDRA terms of interest that also would require further investigation even if the above PRR thresholds have not been reached c. Apply other more specific queries as appropriate (e.g. allowing filtering for subgroups of interest etc.). For detailed recommendation and advice on queries, which allow further analyses please refer to the DWH tutorials; see References) d. Investigation and access to the individual reports can be achieved via the drill functionalities available on the individual queries, to assess the clinical relevance of the potential signal e. Performing the specific query that investigates possible interaction of the product with other products being used with the same animal (at least yearly) The DWH also allows a user to automatically receive pre-defined queries at pre-defined intervals. 4.3. Time periods for routine assessment The Committee for Medicinal Products for Veterinary Use (CVMP) determines at the time of adoption of an opinion to grant a new marketing authorisation for a centrally authorised product and/or in case of significant changes to the marketing authorisation, whether to follow the standard time periods for routine assessment (see Table 1 below), which is generally foreseen, or whether other surveillance intervals or more intensive monitoring is required. The CVMP may also decide to reduce the requirements for routine assessment for a specific product. The following routine surveillance intervals are based on experience gained to date with the procedure in place involving monthly surveillance of expedited adverse events for centrally authorised products. The following proposals are continuing to be developed and will be evaluated in due course. Table 1: Routine surveillance intervals 3-monthly For products up to 2 years following initial placing on the market or following authorisation of e.g. a significant new indication, addition of a new target species or sub-group/age-group etc., as recommended by CVMP 6-monthly For the next 2 years Yearly Thereafter EMA/CVMP/PhVWP/471721/2006 Page 6/9
188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 4.4. Intensive monitoring Intensive monitoring occurs with the same methodology and procedures as described above however in time frames that are shorter than for products under routine monitoring. The time periods for intensive monitoring are risk based and based on DWH query outcomes. The proposal for surveillance frequency will be agreed on by the CVMP and may have been recommended by the CVMP Pharmacovigilance Working Party (PhVWP-V) on an ad-hoc basis. Reasons for recommending intensive monitoring may be related to the following: Known class related safety concerns under special surveillance Specific data available from the marketing authorisation dossier which may require specific post marketing follow-up Safety concerns or concerns on lack of expected efficacy raised following the analysis of EVVet data or data contained in Periodic Safety Update Reports (PSURs); Safety concerns or concerns on lack of expected efficacy or regulatory measures having occurred in a third country etc. 4.5. Monitoring of adverse events in humans having occurred in a third country Third country events eligible for expedited reporting are sent directly by a marketing authorisation holder to EVVet and are therefore not assessed by any of the EU Member States competent authorities at the time of data entry. In order to ensure adequate surveillance it has been decided that specific monitoring of adverse events in humans having occurred in a third country is required. The Agency will screen on a weekly basis all human adverse events for all centrally authorised products having occurred in a third country and will immediately inform the respective rapporteur on any specific and important observations that may have been reported to EVVet. Criteria for selection on a case by case basis of reports to be forwarded are derived from Directive 2001/83/EC (definition for serious [human] adverse reactions): an adverse reaction [in humans] which results in death, is lifethreatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or a congenital anomaly/birth defect. The rapporteur will retain overall responsibility and evaluate the information to decide whether to include the information in the routine analysis at the next time point or whether to inform the CVMP for consideration of possible urgent action in order to safeguard public health in the EU. 5. Surveillance management procedures - roles and responsibilities in surveillance of centrally authorised products Different regulatory bodies and personnel are involved in surveillance of EVVet data on adverse events involving centrally authorised products, including: the rapporteur, pharmacovigilance expert (PhV expert), PhVWP-V, CVMP and the Agency. Not only analysis and assessment of data but transparency and communication of surveillance results and outcome are of crucial importance. Therefore surveillance results as well as their updates will be collated in an electronic document exchange and tracking facility, which is provided by the Agency and accessible for the rapporteur/phv expert, PhVWP-V and CVMP. EMA/CVMP/PhVWP/471721/2006 Page 7/9
228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 Roles and responsibilities for all regulatory personnel and the Agency, involved in surveillance procedures for centrally authorised products, are described as follows. 5.1. The rapporteur supported by pharmacovigilance expert(s) (PhV expert(s)) The rapporteur supported by pharmacovigilance expert(s) (PhV expert(s)) will: Perform EVVet data analysis on centrally authorised products or active substances at time periods agreed on by the CVMP Perform EVVet data analysis in line with the methodology described above Evaluate and assess the analysed data (expectedness, strength of possible signal, urgency). Use the safety profile of the centrally authorised product, monitored group of veterinary medicinal products or active substance, knowledge from PSURs and information already stored in the tracking facility for assessment Recommend future surveillance frequency intervals to the CVMP and, if applicable, recommend action e.g. targeted PSUR, request for specific pharmacovigilance data or post-authorisation safety studies, change to the product literature, non-urgent information (NUI) request, rapid alert (RA) etc. Record the outcome and the recommendation(s) from evaluation of EVVet data in the tracking facility. Update the tracking facility with the conclusions from the PhVWP-V and CVMP, as applicable Perform evaluation of third country reports for human adverse events involving centrally authorised products, specifically forwarded by the Agency following weekly EVVet screening Inform the CVMP directly of urgent matters that may arise from the analyses. 5.2. The CVMP Pharmacovigilance Working Party (PhVWP-V) The PhVWP-V: Discusses as a standing item on its agenda, the observations and recommendations that are recorded by the rapporteur or PhV experts in the tracking facility. Depending on the urgency of the issue ad hoc meetings may be arranged. Recommends action, when necessary, to the CVMP, affecting the authorisation status, availability and/or necessary improvements to the product literature, gives advice, when requested by the CVMP, on future surveillance frequency and/or on the need for regulatory action(s). 5.3. The Committee for Medicinal Products for Veterinary Use (CVMP) The CVMP: Is informed of the outcome of the discussions and conclusions occurring in the PhVWP-V Discusses and decides on action, when required, for specific items that were forwarded directly by the rapporteur/phv expert or the PhVWP-V May conclude that further investigations are necessary which may require input from the marketing authorisation holder EMA/CVMP/PhVWP/471721/2006 Page 8/9
265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 May conclude at any stage to alter the surveillance interval for a product, to increase or decrease the frequency of the analysis. 5.4. The Agency The Agency supports and coordinates the process as follows: Making available, supervising and being responsible for the functionalities of the DWH by providing the necessary technical tools to the stakeholders Ensuring recoding of the data related to centrally authorised products (automatic and manual recoding of product information in reports to centrally authorised products information in the product database) Developing and making available safety profiles for all centrally authorised products in the tracking facility. A safety profile includes the relevant SPC and product literature safety information as well as the corresponding VeDDRA terms. It also includes information on significant changes to the marketing authorisation and marketing dates, from PSURs and any relevant scientific or regulatory information available related to the safety and or lack of expected efficacy of the product Developing and making available a tracking facility that enables recording and summarising the outcome of the analysis, assessment, recommendations and the safety profiles, which is accessible to the CVMP, PhVWP-V, rapporteurs and PhV experts Performing duplicate detection analysis reports Maintaining the overall processes described for surveillance and providing technical support in adequate time frames to rapporteurs and PhV experts when requested Initial screening of third country reports received via EVVet for human adverse events related to the use of a centrally authorised product. 6. References and links to websites EudraVigilance Veterinary (EVVet) DataWarehouse (DWH) tutorials (to be developed) EudraVigilance Access Policy For Medicines For Veterinary Use (draft released for public consultation). http://www.ema.europa.eu/pdfs/vet/euleg/11370008en.pdf European Commission - The Rules Governing Medicinal Products in the European Union, Volume 9. Brussels: European Commission; June 2004. Pharmacovigilance. Part II Veterinary medicinal products. To be replaced by Volume 9B. European Parliament and Council (2001) - Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products. http://eur-lex.europa.eu/en/index.htm. European Parliament and Council (2001) - Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. http://eur-lex.europa.eu/en/index.htm. European Parliament and Council (2004) - Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. http://eur-lex.europa.eu/en/index.htm. EMA/CVMP/PhVWP/471721/2006 Page 9/9