Applies to: Scientific Administrators in the Signal Detection and Data Analysis Section, Pharmacovigilance and Risk Management Sector

Transcription

1 Work instructions Title: Screening electronic reaction monitoring reports (ermr) for new signals Applies to: Scientific Administrators in the Signal Detection and Data Analysis Section, Pharmacovigilance and Risk Management Sector Status: PUBLIC Document no.: WIN/H/3406 Lead Author Approver Effective Date: 19-SEP-12 Name: Cosimo Zaccaria Name: Georgy Genov Review Date: 19-SEP-15 Signature: ON FILE Signature: ON FILE Supersedes: N/A Date: 14-SEP-12 Date: 17-SEP-12 TrackWise record no.: Changes since last revision New WIN. 2. Records The non-formatted ermr to be produced with the new data corresponding to the period of interest (called the reference period throughout this document) and saved in DREAM by a Data manager of the Data Collection and Management (P-PV-DCM) section. The folder contains one file for each Signal Validation Team (SVT) member. The files are named: For every 2 weeks monitored products (IM): IM Name of validator version - date.xls For once-monthly monitored products (RM): RM Name of validator version - date.xls and saved in DREAM in the following location: Cabinets/13. Projects/EudraVigilance - NEW STRUCTURE/Pharmacovigilance/Data Analysis/SAS analysis/signal Validation Team - Reaction Monitoring Reports/eRMR_SDA The formatted Excel file to be used for the review of the ADRs reported (called the Excel ermr throughout this document) named: For every 2 weeks monitored products (IM): IM_Name of validator.xls For once-monthly monitored products (RM): RM_Name of validator.xls. 7 Westferry Circus Canary Wharf London E14 4HB United Kingdom Telephone +44 (0) Facsimile +44 (0) info@ema.europa.eu Website An agency of the European Union European Medicines Agency, Reproduction is authorised provided the source is acknowledged.

2 and saved in DREAM in the following location: Cabinets\Old EDMS Structure\Operational Units\Human\Post\PHVSE\H-Pharmacovigilance\Signal detection PhV and PASE\IM RM CAP list\ermrs since May 2011 Signal Notifications sent by each SVT member are stored in electronic format in the mailbox: Public Folder/Chrono In/ S/H-SD (H-SD) All signals are listed in the Signal Detection Tracking Table named SDMB-IM_RM 2.xls which is located in DREAM in: Cabinets\Old EDMS Structure\Operational Units\Human\Post\PHVSE\H- Pharmacovigilance\Signal detection PhV and PASE\IM RM CAP list. 3. Instructions This WIN provides a guidance on how to screen the ermr and refers to: SOP/H/ Periodic signal detection for centrally authorised products based on reaction monitoring reports - which states that the screening of the ermr is performed by SVT members. WIN/H/3287 Evaluation, validation, prioritisation, and reporting signals from the review of CIOMS forms and line listings - after identification of signals screening the Reaction Monitoring Report. This WIN also provides instructions on how to send Signal Notifications in a standardised format to H- SD mailbox for validation. These instructions are applicable to once-monthly monitored (RM), every 2 weeks monitored (IM) products and weekly monitored products in special situation (i.e. pandemic) This WIN consists of six individual chapters: I. Excel ermr File management II. III. IV. Structure of the Excel ermr file Structure of the ermr worksheet Screening the ermr V. Validation of new signals VI. VII. Guidance for key activities in screening the ermr Processes in place in case of SVT member s absence I. Excel ermr File Management As described in SOP/H/3243 Creation of the reaction monitoring reports for signal detection activities ermrs are generated by the P-PV-DCM section and forwarded by the Data Manager to the H-SD mailbox on Wednesday of the week preceding the Signal Validation Meeting (SVM) for IM or RM products. The SDA secretariat saves and imports the ermr on behalf of SVT member following the steps described below: WIN/H/3406, 19-SEP-12 Page 2/23

3 1. Receiving the ermr When the new ermrs are created by P-PV-DCM, an is sent to H-SD by the P-PV-DCM manager. The message contains the locator to the folder in DREAM which contains all nonformatted ermrs. The updated ermrs include the new cases received in EudraVigilance during the reference period (mentioned in the subject of the ). In case of a technical problem, the Data Manager informs H-SD of the delay. 2. Importing the ermrs in DREAM SDA secretariat imports for each SVT member the non-formatted ermrs in the formatted Excel ermr file saved in DREAM and then the files are all checked-in to be unlocked. Once the files are prepared the SDA secretariat sends an to all SVT members and lets them know that the Excel ermrs files are ready for the screening. 3. Check-out and Check in the Excel ermr file in DREAM Each SVT member checks-out the ermr file in DREAM for editing. Once the screening is finalised the SVT member checks-in the Excel ermr file in DREAM. It is a good DREAM practice and it is advisable that SVT members keep the Excel ermr files checked-in while not working on them to avoid any inconvenience in case of an absence. 4. Exporting the ermrs in G:drive The SDA secretariat sends the reminders via Outlook to each SVT member specifying by when all Excel ermr files have to be checked-in for the update (usually a day before P-PV-DCM produces the new ermr which is on a Monday, except when the Monday is a EMA holiday). SDA secretariat double-checks whether or not all files are checked-in in DREAM; if this is not the case, the SDA secretariat re-contacts the concerned SVT members with a new reminder. Once all Excel ermrs files are checked-in, the SDA secretariat saves them on the G:drive and locks them out to prevent any editing while they are being updated. II. Structure of the ermr The Excel ermr file is a formatted Excel file which contains 4 different worksheets named: 1. ermr : contains ICSRs historically submitted to EV plus new ICSRs submitted during the reference period. WIN/H/3406, 19-SEP-12 Page 3/23

4 2. EVDAS : contains hyperlinks to the standard EVDAS simplified queries to support signal detection activities such as direct access to electronic line listings, calculation of the dynamic Proportional Reporting Ratio (PRR) etc. 3. Drug info : this worksheet is automatically updated every 6 months. It is populated with the most used information related to a given active substance, as follows: a. Active substance b. Medicine name c. ATC code d. Marketing Authorisation Holder e. Status : authorised/withdrawn/suspended f. Authorisation date g. Indication h. Classification : conditional approval / exceptional circumstances / orphan / generic / biosimilar i. EPAR: (optional) direct hyperlink to the latest SmPC published on the EMA website (manual entry is required) j. PSUR-AR: (optional) direct hyperlink to the latest PSUR- assessment report (AR) in DREAM (manual entry is required) WIN/H/3406, 19-SEP-12 Page 4/23

5 4. Legend : contains the full list of SMQs (according to the latest version of MedDRA) sorted by alphabetic order with the related acronyms and the legend for all drop-list menus. III. Structure of the ermr worksheet The ermr worksheet is used to perform the screening of new potential signals or to check whether a risk for a specific drug-event combination has changed. It allows a comparison between the reference period and the cumulative history of all ICSRs submitted to EV (total) for a given active substance (or combination of active substances). The figures displayed in the columns of the ermr are computed from the EudraVigilance Post- Authorisation Module (EVPM) and the EudraVigilance Clinical Trials Module (EVCTM). Data in EVPM include reports classified as EVPM ICSRs 1, EVPM backlog ICSRs 2, EVPM Master ICSRs 3, PSUR ICSRs 4, Master PMPSUR 5. 1 ICSRs transmitted to the EudraVigilance Post-Authorisation Module (EVPM) 2 ICSRs transmitted retrospectively to EVPM WIN/H/3406, 19-SEP-12 Page 5/23

6 Data in EVCTM include reports classified as EVCTM ICSRs 6, EVCTM backlog ICSRs, ASR ICSRs 7, Master CTICSR 8, Master CTASR 9. The structure of the ermr is as follows: A. PT Code : MedDRA Preferred Term Code. These codes are used only for the production of the ermr and the column can be hidden; B. Active Substances : This column contains the active substances (or combination of active substances) allocated to each SVT member; C. SOCs : MedDRA System Organ Class classification; D. HLGTs : MedDRA High Group Level Term classification; E. HLTs : MedDRA High Level Term classification; F. SMQ Narrow : Standardised MedDRA Query (narrow) classification. This column contains: a. Empty cells when the MedDRA PT is not associated with any SMQ; b. One single SMQ per cell when the MedDRA PT is associated with one unique SMQ; c. Different SMQs in one single cell when the MedDRA PT belongs to more than one SMQ (the different SMQs are separated by -- ). G. SMQ Broad : Standardised MedDRA Query (broad) classification. This column is organised as above for the SMQ narrow. H. PTs : MedDRA Preferred Terms classification; I. IME/DME : This column indicates Important Medical Events and Designated Medical Events ; J. New EV : Number of new cases received in EVPM and EVCTM for the concerned drug-event combination during the reference period; K. Tot EV : Total number of cases received in EVPM and EVCTM for the concerned drug-event combination, including the reference period; The columns from L. New Fatal to Y. Tot Serious refer to the number of cases received in EVPM and EVCT: L. New Fatal : Number of fatal 10 cases received for the concerned drug-event combination during the reference period; 3 Master ICSRs created after duplicate detection, transmitted to EVPM 4 ICSRs from Periodic Safety Update Reports transmitted to the EVPM 5 Master ICSRs from PSURs created after duplicate detection, transmitted to EVPM 6 ICSRs transmitted to the EudraVigilance Clinical Trial module (EVCTM) 7 ICSRs from Annual Safety Reports transmitted to the EVCTM 8 Master ICSRs created after duplicate detection, transmitted to EVCTM 9 Master ICSRs from Annual Safety Reports created after duplicate detection, transmitted to the EVCTM WIN/H/3406, 19-SEP-12 Page 6/23

7 M. Total Fatal : Total number of fatal cases received for the concerned drug-event combination, including the reference period. When the number of fatal cases is 1 the font automatically turns red; N. New Med Err/Abus : Number of cases received for the concerned drug-event combination during the reference period and reported with at least one reaction contained in the ad-hoc SMQ Medication Error/Abuse. The ad-hoc SMQ is reported in the worksheet Legend and contains the following MedDRA PTs: a. HLGT Medication error ; b. Selected MedDRA PTs of the SMQ Depression and suicide/self-injury ; c. Selected MedDRA PTs of the SMQ Drug Abuse, dependence and withdrawal ; O. Tot Med Err/Abus : Total number of cases received for the concerned drug-event combination, including the reference period and reported with at least one reaction contained in the ad-hoc SMQ Medication Error/Abuse. P. New Paed : Number of cases referring to patients aged < 18 years old and received for the concerned drug-event combination during the reference period; Q. Total Paed : Total number of cases referring to patients aged < 18 years old and received for the concerned drug-event combination, including the reference period; R. New Geriatr : Number of cases referring to patients aged > 65 years old and received for the concerned drug-event combination during the reference period; S. Total Geriatr : Total number of cases referring to patients aged > 65 years old and received for the concerned drug-event combination, including the reference period; T. New EEA: Number of cases originating from the European Economic Area (EEA) 11 and received for the concerned drug-event combination during the reference period; U. Total EEA : Total number of cases originating from the EEA and received for the concerned drugevent combination, including the reference period; V. New HCP : Number of cases originating from a Health Care Professional (HCP) 12 and received for the concerned drug-event combination during the reference period; W. Total HCP : Total number of cases originating from a HCP and received for the concerned drugevent combination, including the reference period; X. New Serious : Number of cases reported as Serious 13 and received for the concerned drugevent combination during the reference period; 10 A case is considered fatal if either the E2B field A (Result in Death) has the value Yes or the E2B field B.2.i.8 (Outcome) has the value Fatal 11 A case is considered originated from the European Economic Area if the E2B field A.1.1 (Primary Source Country) has a country belonging to the European Economic Area (EEA) 12 A case is considered originated from a Health Care Professional if the E2B field A (Qualification) has at least one of the following values: Physician, Pharmacist or Other health professional 13 A case is considered serious if the E2B field A (Serious) has the value Yes WIN/H/3406, 19-SEP-12 Page 7/23

8 Y. Total Serious : Total number of cases reported as Serious and received for the concerned drug-event combination, including the reference period; Z. New Spontaneous : Number of spontaneous cases received in EVPM (including report types not available to sender (unknown) and others ) for the concerned drug-event combination during the reference period; this number does not include the new reports from observational studies (see column AK. New Obs ); AA. Total Spontaneous : Total number of spontaneous cases received in EVPM (including report type not available to sender (unknown) and others ) for the concerned drug-event combination, including the reference period; this number does not include reports from observational studies (see column AL. Tot Obs ) Note that: this number is used for the calculation of the PRR and the SDR columns; AB. PRR (-) : 95% confidence interval lower bound of the PRR for the concerned drug-event combination using all other drug-event combinations available in the database as reference. When the SDR criterion is met 14, the cell is automatically highlighted in red; AC. PRR : value of the Proportional Reporting Ratio (PRR) for the concerned drug-event combination, using all other drug-events combination available in the database as reference; AD. Priority : this column groups together filters belonging to the column Changes, IME/DME, Paediatric and SDR. It facilitates the selection of drug-event combinations according to three mutually-exclusive priority levels defined as follows: b. Priority 1: highest priority. It indicates drug-event combinations received in the reference period classified as DME; c. Priority 2: It indicates drug-event combinations received in the reference period (not included in the priority 1) classified as IME with an SDR; d. Priority 3: It indicates drug-event combinations received in the reference period (not included in the priority 1 and 2) with a fatal outcome as well as paediatric or parent-child reports. AE. Changes : column that indicates all drug-event combinations for which new ICSRs (initial or follow-up) were received in both EVPM and EVCT module during the reference period. By selecting one of the values in the drop-down list, 3 different filters can be applied: New : drug-event combinations appearing in EV for the first time ; Increased : drug-event combination with an increased number of cases in the column Tot EV or for which a follow-up report was received since the previous ermr; Increased fatal : drug-event combinations with an increased number of fatal cases or for which a follow-up for a fatal case has been received; 14 The Statistics of Disproportionate Reporting is calculated differently according to the periodicity of the ermr. For biweekly ermrs (IM) the criterion is met when the number of spontaneous cases is > 3 and the PRR (-) is > 1. For monthly ermrs (RM) the criterion is met when the number of spontaneous cases is > 5 and PRR (-) is > 1. WIN/H/3406, 19-SEP-12 Page 8/23

9 AF. SDR : column that allows identifying drug-event combinations with a signal of disproportionate reporting i.e. PRR (-) > 1 with 3 or more spontaneous cases for IM products, 5 or more spontaneous cases for RM products. When these criteria are met, the term SDR (n) appears in the column where n is the number of instances the drug-event combination was recognised as an SDR; AG. Signal Status : This filter allows the SVT member qualifying a drug-event combination. Only the following terms can be used: Listed: MedDRA PT reported in the SmPC (section 4.8) for at least one brand name of a concerned active substance. This entry is automatically updated every 6 months and it concerns Centrally Authorised Products (CAPs) only. US: MedDRA PT which is listed in the United States Prescribing Information (US-PI) of a concerned active substance. This optional entry is manual. Linked: MedDRA PT linked to another MedDRA PT already qualified in the column Signal Status as a validated signal or Listed. (See chapter IV: how to link different MedDRA PTs ). Ongoing: MedDRA PT under review from a previous screening of the ermr. Closed: MedDRA PT closed according to the decision at the Signal Validation Meeting (SVM). This should be followed by populating the column Comment with the conclusion sent to H- SD. Monitor: MedDRA PT under monitoring according to the decision at the SVM. This should be followed by populating the column Comment with the conclusion sent to H-SD. PSUR: MedDRA PT monitored in PSURs and acknowledged as such by the Rapporteur. This should be followed by populating the column Comments with the Rapporteur s conclusion of the PSUR-AR. RMP: MedDRA PT included in the Risk Management Plan as Identified or Potential Risk. This entry is manual until the validated Annex 1 of the RMP will be automatically implemented. Disease: MedDRA PT which is considered to be part of the underlying disease / indication; Other: MedDRA PT flagged as Priority 1, 2 or 3 but according to the SVT member s judgement a review of the cases is unlikely to substantiate the signal. Check: when none of the above-mentioned filters is applicable and therefore a review of the cases / line listing is expected. This should be followed by populating the column Comments with the date and the action expected (e.g. review of cases / line listing). AH. Comments : General comments filled in by the SVT member as free text after qualifying a MedDRA PT using the abovementioned filters options in the column Signal Status. (See chapter VI: how to populate the column comment ) AI. New Lit : Number of cases originating from literature reports received in EV for the concerned drug-event combinations during the reference period. When the number of cases is > 1 in the column New Lit the cell is automatically highlighted in blue; AJ. Tot Lit : Total number of cases originating from literature reports received in EV (EVPM and EVCTM) for the concerned drug-event combination including the reference period; AK. New Obs : Number of cases originating from solicited reports received in EVPM for the concerned drug-event combination during the reference period. (These cases are not included in the New Spontaneous cases); WIN/H/3406, 19-SEP-12 Page 9/23

10 AL. Tot Obs : Total number of cases from solicited reports received in EVPM for the concerned drugevent combination including the reference period. (These cases are not included in the Total Spontaneous cases nor in the calculation of the PRR); AM. New CT : Number of cases originating from interventional clinical trials received in EVCTM for the concerned drug-event combination during reference period; AN. Total CT : Total number of cases originating from interventional clinical trials received in EVCTM for the concerned drug-event combination including the reference period. (These cases are not included in the calculation of the PRR); AO. RoA 1 : Name of the most frequently reported route of administration for the concerned drugevent combination; AP. New RoA1 : Number of cases received in EV for the concerned drug-event combination and the most frequently reported route of administration during the reference period; AQ. Tot RoA1 : Total number of cases received in EV for the concerned drug-event combination and the most frequently reported route of administration, including the reference period; The columns from AR. Roa2 to AW.Tot RoA3 (which are named RoA2, New RoA2, Tot RoA2, RoA3, New RoA3 and Tot RoA3 ) contain the second and the third most frequently reported route of administrations for the concerned drug-event combination; AX. New RoA (n/a) : Number of cases received in EV for the concerned drug-event combination in which the route of administration was unknown ( unk ) or missing ( n.a. ) during the reference period; AY. Tot RoA (n/a) : Total number of cases received in EV for the concerned drug-event combination in which the route of administration was unknown ( unk ) or missing ( n.a. ), including the reference period; AZ. Brand Name 1 : Corresponding to the CAP 1. The column Brand name 1 contains the brand name reported the most frequently; BA. New Brand 1 : Number of cases received in EV during the reference period for the concerned brand name and the corresponding MedDRA PT; BB. Tot Brand 1 : Total number of cases received in EV for the concerned brand name and the corresponding MedDRA PT including the reference period; BC. PRR(-) Brand 1: 95% confidence interval lower bound of the PRR for the concerned brand name and the corresponding MedDRA PT, using all other brand names and all other MedDRA PTs available in the database as reference. When the SDR criterion is met (see footnote 14 page 9), the cell is automatically highlighted in red; BD. Freq SPC Brand 1 : as reported in the SmPC in 4.8 for the concerned brand name, when available; BE. Brand Name (n) : columns repeated as from AZ to BD according to the number of brand names authorised in the EEA under the same active substance; the columns Brand name (n) are sorted following a decreasing order of reporting. WIN/H/3406, 19-SEP-12 Page 10/23

11 IV. Screening the ermr 1. Step I = CHECKING-OUT THE EXCEL ermr FILE: following the sent-out by the SDA secretariat (informing that the Excel ermrs files are updated and ready for the screening) checkout the file in DREAM; 2. Step II = SELECTING THE REACTION MONITORING REPORT: to select the reaction monitor report for the period of interest set the filters on not Blanks in the column Changes, this filter shows all drug-event combinations received during the reference period. 3. Step III = CHECKING MONITORED ISSUE: in the column Signal Status set the filters on Monitor to double-check whether or not there are new cases or follow-ups related to the drugevent combination under monitoring. If this is the case replace the status Monitor by Check which means that only new cases will be reviewed. As a general principle each drug-event combination marked as monitored in the column Signal Status should be replaced by Check for the review of any new case unless it is specified in the column Comments that a Follow-up in the upcoming PSUR is expected. 4. Step IV = SCREENING DMEs: in the column named Priority, set the filter on Pr1 in order to display all drug-event combinations classified with the highest level of priority (DMEs). Each DME shall be either assigned a Signal Status by selecting one of the available filter options (described in chapter III) or justification for not assigning a Signal Status shall be provided in the column Comment (e.g. review when additional cases become available). THIS IS A MANDATORY STEP FOR ALL ermrs. 5. Step V= SCREENING THE REMAINING MedDRA PTs: in the column Priority set the filters on Pr2 and Pr3 to perform the screening of the remaining drug-event combinations not included in step IV. Investigation and justification of the MedDRA PTs classified with these two priority levels are based on SVT member s clinical judgement. 6. Step VI = TRANSMISSION OF SIGNAL NOTIFICATION TO H-SD: When the filter Check is applicable a review of the cases is expected specifying in the column Comments whether the review of the cases or the line listing is needed. Set the filter on Check in the column Signal Status to select all drug-event combinations for which further investigation is required. If the signal was previously reviewed specify in the column Comments that only the review of new cases is needed. Select the area of the table which includes all columns between Active substance and Comments ; copy and paste in an to be sent to H-SD. In order to facilitate the work of the SDA secretariat and the retrieval of messages, indicate in the Subject of the Signals - SVT member s name - RM or IM Reference period. WIN/H/3406, 19-SEP-12 Page 11/23

12 7. Step VII = UPDATING THE ermr: after the SVM, update the ermr in line with the conclusions adopted for the concerned signals. The column Signal Status should reflect the decision taken at the meeting using the filters Closed, Monitor or Rapp. The column Comments should reflect the conclusion sent to H-SD in the report. 8. Step VIII = CHECKING-IN THE ermr IN DREAM: save the Excel ermr file and check it in. N.B. Identification of signals should be based on all available information which can be visualised by selecting in the Menu bar: [Sort&Clear Clear]. Judgment should be exercised and information of clinical relevance should be identified, even if it does not represent an IME/DME or a SDR. V. Validation of new signals Once new signals have been identified, their validation is a matter of clinical judgment and the following elements should be considered: 1. Clinical relevance i. Severity of the reaction and its outcome: Depending on the suspected medicinal product and the concerned adverse reaction, reactions leading to a fatal outcome or irreversible serious reactions should be considered in priority for inclusion in the list of signals to be validated; unless there is a suspected relationship with the underlying disease or if this outcome is already mentioned in the product information. ii. Novelty of the reaction: New and (medically) serious reactions should be reviewed, as well as new aspects of a known issue. DMEs or events of special interest that are known to be rare, serious, and highly attributable to drugs should be considered in priority as signals to be validated. This is irrespective of the statistical criteria, or whether there is a high degree of biological plausibility (for example an anaphylactic shock, or a toxic epidermal necrolysis). iii. Clinical context: The reaction PT should always be considered in the broader context of a possible drug-induced toxicity or more complex syndrome (e.g. interval QT prolonged may suggest the occurrence of torsades de pointe, hepatitis may suggest the occurrence of other types of liver injuries, JC virus infection may reflect the occurrence of progressive multifocal leukoencephalopathy). The SVT member should (1) check in EudraVigilance whether other case reports involving relevant terms associated with the syndrome or the system organ class have previously been transmitted to EudraVigilance and, if this is the case, (2) assess whether these clinical entities should be included in the signal identification process. iv. Potential for drug-drug interactions: medicinal products susceptible to induce clinically relevant drug-drug interactions should be subject of a specific, targeted monitoring. The (co)-suspected medications could be checked for these medicinal products in the line listing. v. Reactions in special populations, eg. paediatrics vi. Events related to the indication of the medicinal product (e.g. thrombosis following an antithrombotic agent) should not, in principle, be considered as signal unless cases of lack of efficacy or loss of efficacy need to be investigated. 2. Previous awareness i. In principle, an adverse reaction which is already listed in section 4.4 or 4.8 of the Summary of Product Characteristic (SPC) or which has already been assessed by the CHMP / Rapporteur in the PSURs or RMP, does not represent a new signal. However, it may qualify as such if its apparent frequency of reporting, its temporal persistence, its severity, or change in the outcome or reported WIN/H/3406, 19-SEP-12 Page 12/23

13 fatality rate, suggests a new information as compared to the data included in the SPC or previously assessed by the Rapporteur. ii. The European Pharmacovigilance Issues Tracking Tool (EPITT) should be checked to verify if a signal has already been addressed within the EU regulatory network. iii. The SVT Member should also verify whether there is new information available from the MAH, or recent decisions (e.g. request of additional information or ongoing type II variation) taken by the Rapporteur or the CHMP, already addressing the signal. This can be done by searching in the Product Cabinet in DREAM, in SIAMED or by enquiring with the Product Team Leader (PTL). i.v. The granularity effect of the medical dictionaries utilised for data coding and the variability of the terms employed among healthcare professionals to characterise the same symptoms or diagnoses should be considered when appraising the novelty of a signal. The concerned safety issue could well be reported under several distinctive PTs and included in the SPC as a more general term as it is often the case for hepatic reactions or hypersensitivity for example. v. If an adverse reaction is a monitored signal in the Signal Detection Tracking Table for a specific active substance or medicinal product, every new case should in principle be appraised until the signal has been closed. 3. Statistical criteria i. In principle, a minimum of at least 3 (for IM) or 5 (for RM) spontaneous cases should have been reported to EudraVigilance in order to consider the adverse reaction of interest as a signal. The number of new cases should also be considered if the signal has already been reviewed and included in the Signal Detection Tracking Table. This threshold may not apply for some reactions (eg. anaphylactic shock) or for orphan drugs. ii. A PRR (-) > 1 and 3 (for IM), 5 (for RM) or more reports defines a signal of disproportionate reporting. In this case it simply expresses a higher reporting than expected of the adverse reaction for the active substance of interest compared to all other active substances in the database. iii. The disproportionality analyses are performed on spontaneous reporting system databases and therefore are affected by the same strengths and weaknesses (including the therapeutic area in which the medicinal product is used, the variability of use across countries of the medicinal product, or the strong reporting association of the concerned adverse reaction with another medicinal product (masking effect)). Various biases or reporting artefacts may affect the value of the PRR and generate false positives or false negatives. Therefore, the absence of a Signal of Disproportionate Reporting (SDR) does not necessarily exclude the possibility of a causal association between the concerned medicinal product and the adverse reaction. Alternatively a high SDR does not always reflect a causal association between a medicinal product and the adverse reaction. VI. Guidance for key activities in screening the ermr 1. How to select the Reaction Monitor Report To display the reaction monitor report for the reference period use the ermr worksheet: WIN/H/3406, 19-SEP-12 Page 13/23

14 The ermr worksheet contains the Cumulative Summary Table of ADRs for the concerned active substance (or combination of active substances) since the first ICSRs was received in EV. To display the cases received during the reference period, select the column Changes and set the filters on not Blanks. The ermr will display all reports received during the period of interest for the three categories: new, increased fatal and increased. The figures showed on the bottom left corner of the worksheet are the number of ADRs received in the ermr (which need to be screened) and the total number of ADRs received in EV: 2. How to group and ungroup columns The ermr contains many columns. To better organise the information in the ermr and to simplify its review it is possible to visualise only the columns which the SVT member is interested in. By default the visualisation can be done as follow: To ungroup and visualize all columns belonging to a specific category click on the symbol above the header: WIN/H/3406, 19-SEP-12 Page 14/23

15 To group again the columns click on the symbol above the header: The grouping and ungrouping of columns can be customised according to the preferences of the SVT member or it can be deleted to allow the visualisation of the full categories: in Excel the options are on the Data tab located in the Ribbon, under the Group or Ungroup button located in the Outline Group. 3. How to prioritise the review of drug-event combination without using the Column Priority Grouping of drug-event combinations by applying filters allows the screening to focus on specific types of ADRs. After displaying the reaction monitor report the following could be selected: Pr1/Pr2/Pr3: the column Priority groups together the filters that are applicable in the following columns: IME/IME, Changes, SDR, Fatal, Paediatric. To select the priority of interest: DME/IME = in the column IME/DME un-tick the filter Ime and Blank to select designated medical events only and press ok : WIN/H/3406, 19-SEP-12 Page 15/23

16 To prioritise by important medical event only, un-tick Dme and Blanks and keep ticked Ime and Ime/Dme and press ok. To select both Ime and Dme keep un-ticked only Blanks and press ok. New ADRs = set the filter on New in the column Changes. The ermr will only show drugevent combinations which are appearing for the first time in EV in the column Tot EV : Increased fatal ADRs = set the filter on Increased fatal in the column Changes. Apply this filter to select all drug-event combinations with a fatal outcome or for which a follow-up for a fatal report has been received during the reference period; Increased ADRs = set the filter on Increased in the column Changes to select all drug-event combinations with an increase in number of cases or with a new follow-up report received in the reference period; SDR = in the column SDR un-tick the filter Blanks and press ok ; the ermr will show automatically all drug-event combinations which have reached an SDR in the ermr. This filter can be combined with Ime to prioritise by important medical event with an SDR: Customised thresholds: in the column Tot Spontaneous or in any other column named Tot set the filter to display ADRs received with a minimum number of cases in EV: [ Number filter - > select greater than or equal to and type a number for your threshold for instance 5 in the field option - > ok] A simple way to do so is to un-tick all values which are not of interest in the column named Tot : WIN/H/3406, 19-SEP-12 Page 16/23

17 Brand names: The columns concerning brand names are useful when there is more than one brand name centrally authorised for the same active substance. To filter by a specific brand name un-tick the value blanks in the column Brand name of interest: If the ermr is set on the reference period (using the column Changes as shown above) it will show only drug-event combinations received for the concerned brand name during the reference period. In case you also want to display the historical submitted in EV keep the filter in the column brand name and tick Select all in the column Changes. 4. How to filter by new literature reports received in EV To group all MedDRA PTs for which there has been at least one literature case reported in EV during the reference period, follow the step below: a) [Un-tick the value 0 in the column New Lit ]. b) [Press ok] The ermr will show all new literature reports and the cell will automatically turn blue when the value is > then 1: WIN/H/3406, 19-SEP-12 Page 17/23

18 This approach can be used in any column named New such as New serious, New CT, New Obs etc. to select all new cases received under a specific category during the period of interest. The column New Lit is also useful during the screening of signals under monitoring (or closed) to double-check whether or not new evidence is coming from the literature during the reference period. 5. How to release all filters Filters should be applied with caution in order to avoid missing relevant information. To go back and visualise the totality of the data, select in the Menu bar [Sort&Filter ->Clear] as shown below: 6. Comparison of Totals : The columns reporting the totals of each category allows a comparison with the total number of cases received in EV ( Tot EV ). To compare totals: [Hide all columns containing New and leave all columns containing Tot ] WIN/H/3406, 19-SEP-12 Page 18/23

19 The ermr will show for the concerned drug combination event the proportion of fatal/paediatric/geriatric/serious/hcp etc cases against the Total number of cases received in EV. 7. How to extend a search and display information at the level of the SOC/HLGT/HLT It may be useful to extend the search following the broader structure of MedDRA in order to show all drug-event combinations reported historically in EV at different MedDRA levels. This allows obtaining a wider overview of the issue under investigation as follow: For example, extend at the level of the SOC: a) Release all filter in the ermr and identify the drug-event combination of interest. (The MedDRA PTs under investigations are easily retrievable filtering by Check in the column Signal Status : b) Filter by the correspondent active substance and SOC to which the MedDRA PT belongs to: The ermr will show all MedDRA PTs reported in EV at the level of the SOC selected. The same steps can be followed to filter at the level of the HLGT and HLT in the related columns. WIN/H/3406, 19-SEP-12 Page 19/23

20 This functionality is useful to have a broader overview of the information included in the ermr such as SmPC, PSUR, RMP, previous review etc. when looking for possible explanations (links) for a concerned drug-event combination. Justifying and linking MedDRA PTs at different MedDRA level in the ermr increase knowledge overtime facilitating future reviews. 8. How to filter by SMQ when the MedDRA PT belongs to different SMQs This step is necessary when the MedDRA PT is associated with more than one SMQ. To filter by the SMQ of interest and include all MedDRA PTs: [select the filter in the column SMQ narrow type the name of the SMQ and press ok ] 9. How to link different MedDRA PTs The availability of Signal Status in the ermr allows linking MedDRA PTs. An example is proposed below: a) Identify a drug-event combination that requires further investigation b) Extend the search at the level of the SOC (as described above) and display the information reported in the ermr; c) Release the filter in the column Signal Status and check the listedness for the concerned active substance. d) Link the MedDRA PT of concern to any MedDRA PT either validated as a signal or listed in the SmPC. A MedDRA PT may be linked to another MedDRA PT when the latter has been already qualified in the column Signal Status as listed or as Rapp and covers the former term according to the SVT member s clinical judgment. For instance suicidal ideation may be linked to completed suicide as shown below in the example as it covers a more severe medical concept: WIN/H/3406, 19-SEP-12 Page 20/23

21 10. How to populate the column COMMENTS after the SVT meeting: The column Signal Status allows several filter options as described in chapter III. This column should be populated with free text according to the status of the signal as it appears in the column Signal Status and it should reflect the conclusion adopted at the SVM for each reviewed signal. To facilitate future reviews, when the signal is to be closed/monitored it is convenient to populate as follows: date using the option [control+;] for the automatic entry of the today date); Total number of cases reviewed Total number of cases assessed as valid by the SVT member (i.e. unique cases, sufficiently documented etc.) Brief description of the signal as reported in the conclusion sent to H-SD For signals which need to be monitored or followed-up in the upcoming PSUR-AR, populate the column Signal Status with Monitor and report in the column Comments the conclusion sent to H-SD. Specify FU-PSUR if the signal has to be followed-up in the upcoming PSUR-AR: 11. How to display Listedness The listedness of a concerned product is shown in the column Signal Status. This information is updated automatically every six months by the P-PV-DCM manager. In order to display the listedness of an active substance, follow the steps below: a) Clear all filters in the ermr; b) Select the active substance of interest from the column Active substance ; c) Set the filter Listed in the column Signal Status. This is the simple way to show the listed reaction in the SmPC for the active substance of interest. For a given active substance the MedDRA PT is marked automatically as Listed in the column Signal Status when there is at least one brand name with the concerned MedDRA PT listed in the SmPC. To check in which brand name the MedDRA PT has been listed check the column WIN/H/3406, 19-SEP-12 Page 21/23

22 Frequency. If the cell in the column Frequency is populated it means that the MedDRA PT of interest is reported in the SmPC of the concerned brand name. 12. How to review changes in the risk: Tracking all sources of information in the ermr (i.e. recording outcomes of assessments, importing listedness from the SmPC, PSUR and RMP potential risks) allows comparing new information received with the previous knowledge gathered in the ermr. This could be useful when the safety profile may have significantly changed during the reference period. It is possible to re-open signals previously assessed as Closed by replacing the filter by Check in the column Signal status meaning that a review of the new cases received since last assessment is expected. To check whether or not the risk has changed since last screening of the ermr some criteria may be applied such as: Seriousness : checking the number of cases in the column Total fatal compared to the Tot spontaneous / Tot EV. New Evidence : checking whether there are new cases in the column New Lit meaning that new publications may strengthen the evidence of a signal assessed as closed / monitor. Disproportionality at the level of the Brand Name : when the PRR (-) calculated at the level of the brand name is > 1 the cell automatically turns red. This may indicate an increase in reporting or change in the risk for the concerned product-event combination / route of administration / indication. The same principle can be applied reviewing the RMP information entered in the ermr, in particular for potential risks. VII. Processes in place in case of SVT member s absence This process applies when the SVT member is absent for one or more weeks. The SDA secretariat saves in DREAM on a weekly basis the updated version of the Excel ermr file sent to H-SD by the P- PV-DCM manager. When the SVT member is absent during the review of a specific ermr the retrieval of previous versions is possible following one of the two options below: 1. Retrieval from DREAM = the SVT member visualises and selects from DREAM the version of interest that needs to be screened. [Right-click on the Excel ermr File -> View -> Versions-> Select the version of interest] 2. Retrieval from prior to the absence, the SVT member informs the SDA secretariat specifying which version of the Excel ermr File has to be sent as an attachment by . WIN/H/3406, 19-SEP-12 Page 22/23

23 When the Excel ermr File is updated in DREAM with the new data, the SDA secretariat then sends an to the absent SVT member with the attached version requested. Once the SVT member is back, the different Excel ermr File versions are retrieved and the screening should be done separately. These versions can also be printed for the review on paper as follow: [Select the area of interest -> file -> print area -> set print area -> control + p] In order to report both signal status and related comments to the latest version of Excel ermr saved in DREAM, update it with the results obtained from the screening of the previous version/s of the ermr/s. WIN/H/3406, 19-SEP-12 Page 23/23