Guidelines for Conducting Pharmacovigilance Inspections

Transcription

1 Guidelines fr Cnducting Pharmacvigilance Inspectins 1. Purpse T mnitr cmpliance f registratin/authrizatin hlders with their bligatins in cnnectin with pharmacvigilance and drug safety, the Ministry may undertake direct inspectin f pharmacvigilance systems in accrdance with the applicable regulatry requirements. These inspectins are aimed at evaluating the practices f the registratin/authrizatin hlder and/r the cntract pharmacvigilance service prvider fr pharmacvigilance data management and the relevant systems. These inspectins may be cnducted at a single site r several sites. The inspectins may be rutine r in respnse t specific cncerns. During rutine inspectins, and depending n the scpe f the inspectin, the inspectrs examine whether the pharmacvigilance system, implemented and submitted t the Ministry by the registratin/authrizatin hlder, has been accurately represented. Additinally, any party carrying ut pharmacvigilance activities in whle r in part, n behalf f, r in cnjunctin with the registratin/authrizatin hlder may be inspected, in rder t cnfirm their capability t supprt the registratin/authrizatin hlder s cmpliance with pharmacvigilance bligatins. This guideline prvides an utline f the minimum requirements that may be applied t ensure achievement f pharmacvigilance inspectin gals. 2. Respnsibilities The inspectrs are under bligatin t ensure that any pharmacvigilance inspectins cnducted n behalf f the Ministry are perfrmed in accrdance with this Guideline and currently applicable regulatins. 3. Inspectin Types 3.1 Rutine Inspectins Rutine inspectins may be cnducted in the intervals set by the Ministry. 3.2 Targeted Inspectins Targeted inspectins may be perfrmed when ne r mre f the fllwing arise: Triggers fr the inspectin are identified which d nt relate t specific cncerns abut a prduct s safety r actual nn-cmpliance, e.g.: The registratin/authrizatin hlder has nt previusly been inspected The registratin/authrizatin hlder has placed his first prduct n the market The registratin/authrizatin hlder has recently undergne a merger r takever prcess The registratin/authrizatin hlder has changed his system significantly (e.g., established a new database system, cntracted ut reprting activities t a cntract pharmacvigilance service prvider). Significant issues indicated belw, relating t specific cncerns abut a prduct s safety r actual nn-cmpliance, require an inspectin:

2 Delays in carrying ur r failure t carry ut specific bligatins r fllw-up measures relating t the mnitring f prduct safety, identified at the time f marketing authrizatin. Delays in expedited r peridic reprting. Incmplete reprting. Submissin f pr quality r incmplete Peridic Safety Update Reprts (PSUR). Incnsistencies between reprts and ther infrmatin surces. A change in the risk-benefit balance f the prducts, r failing t reprt such changes. Previus inspectin experience f the inspectrs. Cmpany infrmatin received frm ther authrities. Pr r delayed fllw-up t requests fr infrmatin frm the Ministry. Cmmunicatin f infrmatin t the general public n pharmacvigilance cncerns which cncern the sciety in general, withut giving prir r simultaneus ntificatin t the Ministry. Prduct withdrawal withut ntifying, r adequately ntifying, the Ministry. 3.3 Pharmacvigilance System Inspectin These inspectins are designed t review the suitability f the systems, persnnel, and the physical envirnment, as well as their cmpliance with pharmacvigilance bligatins. Prduct may be used as example during these inspectins t test the system. These inspectins may be rutine r targeted. 3.4 Prduct-Specific Inspectins These inspectins fcus specifically n a given prduct and are usually targeted as a result f triggers that have been identified. 3.5 Inspectin f Cntract Pharmacvigilance Service Prviders Any cntract pharmacvigilance service prvider, carrying ut pharmacvigilance activities in whle r in part n behalf f, r in cnjunctin with, the registratin/authrizatin hlder, may be inspected in rder t cnfirm their capability t supprt the registratin/authrizatin hlder s cmpliance with pharmacvigilance bligatins. 3.6 Unannunced Inspectins Inspectins may be cnducted with r withut advance ntice. 4. Preparatin fr a Pharmacvigilance Inspectin The gals f a pharmacvigilance inspectin will vary depending n the criteria t be applied during the inspectin.

3 The scpe f the inspectin will depend n the nature f the inspectin (rutine/triggered) and n the requirements f the inspectin request. Preparatry wrk fr a pharmacvigilance inspectin shuld invlve cllabratin f the inspectrs cmmissined fr cnducting the inspectin with the relevant departments as necessary. The preparatry wrk shuld als invlve the assessrs f a particular prduct r ther specialist (e.g., Infrmatin Technlgy specialists, depending n the scpe f the inspectin). These experts may als be included n the team when frming the inspectin team. An inspectin plan shuld be prepared in line with the scpe and bjectives f the inspectin. The registratin/authrizatin hlders and/r their cntract pharmacvigilance service prvider may be utsurcing all r a part f their pharmacvigilance and safety assessment bligatins. It is imprtant t ascertain frm the Pharmacvigilance System Overview (PSO), r by btaining additinal infrmatin, rganizatinal charts, cntracts/agreements and standard perating prcedures (SOP), as t hw the pharmacvigilance respnsibilities are divided bth within the cmpany and with ther stakehlders. It is equally imprtant t ascertain where the required infrmatin resides when planning the pharmacvigilance inspectin. Several sites/departments may need t be visited in rder t btain a cmplete view f the pharmacvigilance system f the registratin/authrizatin hlder. Access t the glbal pharmacvigilance database, and prvisin by the registratin/authrizatin hlder f the resurces needed t perfrm searches n this database shuld be agreed in advance with the registratin/authrizatin hlder, prir t the inspectin. Prir t the inspectin, it shuld be checked whether any significant changes have been made t the system that wuld have an impact n the inspectin plan. The data and dcumentatin review that shuld be perfrmed as part f the pharmacvigilance inspectin by general sampling r with respect t a particular prduct r therapeutic area shuld be agreed prir t the inspectin, and shuld be cmpatible with the scpe and bjectives f the inspectin. Additinal data and dcumentatin fr review may als be identified during the inspectin. An adequate sample f data and dcumentatin t underg review shuld be frmed, and may be requested t be prvided t the inspectr(s), as part f the preparatry wrk. The sample size may be decided taking int accunt the fllwing factrs: The rganizatin f the registratin/authrizatin hlder and the distributin f the pharmacvigilance and safety evaluatin tasks. The number f prducts granted registratin/authrizatin. The types f prducts and therapeutic areas. The specific cncerns that need t be addressed during the inspectin. The clinical trials and pharmacepidemilgical studies cnducted by the registratin/authrizatin hlder. Ptential different rigins f the reprts. Issues f nn-cmpliance identified during previus inspectins. The sample shuld give a gd representatin f the registratin/authrizatin hlder s cnduct f pharmacvigilance. If necessary, the Ministry may require the registratin/authrizatin hlder t prvide a Pharmacvigilance System Overview (PSO), utlining the pharmacvigilance system in the frmat described in the appendix, in rder t facilitate the planning and preparatry wrk. The PSO shuld be clear and cncise, if pssible n lnger than twenty five pages excluding appendices. The PSO shuld be submitted in bth hardcpy and electrnic frm. The expressin nt applicable shuld be inserted in apprpriate sectins f the PSO which are inapplicable t the registratin/authrizatin hlder. Where the cmpany has in place a single pharmacvigilance system ntwithstanding the rigin f adverse reactins, it is apprpriate t issue a single PSO. Where different pharmacvigilance

4 systems are emplyed by the cmpany, several PSOs will have t be issued, which may result in several inspectins f the same registratin hlder t inspect his individual systems. Any requests fr data and dcumentatin shuld be made in a timely manner in rder t allw the inspectee(s) t prvide all the requested dcuments fr review by the inspectin team. 5. Cnduct f a Pharmacvigilance Inspectin 5.1 Opening Meeting Befre the start f the inspectin, an pening meeting must take place between the inspectr(s) and in particular the key persnnel f the inspectee(s), fr the purpse f prviding an verview f the inspectin plan. In particular, the fllwing pints shuld be addressed during the pening meeting: The lead inspectr shuld describe the purpse and the scpe f the inspectin. The lead inspectr shuld utline the Regulatins and Guidelines that prvide the basis fr the inspectin, and briefly describe the methds t be used during the cnduct f the inspectin. The item headings in the Pharmacvigilance Inspectin Plan shuld be mutually agreed, and inspectin lgistics shuld be discussed. The lead inspectr shuld re-cnfirm that the resurces, dcuments and means required by the inspectrs are available. The time and date fr the clsing meeting and any interim meetings shuld be cnfirmed. Apprpriate persnnel shuld prvide general infrmatin abut the registratin/authrizatin hlder and/r cntract pharmacvigilance service prvider. The general infrmatin will als include an verview f the rganizatin and ther stakehlders relevant t drug safety, the systems used fr the cllectin, cllatin, evaluatin and reprting f adverse drug reactins, a summary f significant changes, if any, since the previus inspectin, and a summary f significant changes that are planned fr the future. 5.2 Cnduct f the Inspectin/Cllecting Infrmatin and Recrding Observatins Full details f the inspectin activities shuld be prvided in the inspectin plan. Nevertheless, during the inspectin, the inspectr(s) may amend the plan t ensure that the inspectin bjectives are achieved. Sufficient infrmatin t fulfill the inspectin bjective(s) shuld be cllected thrugh examinatin f relevant dcuments and cmputer systems, as well as thrugh the cnduct f interviews with relevant persnnel. If access t recrds r cpying f dcuments is refused fr any reasn r there is any withhlding f dcuments r denial f access t areas t which the inspectr has a legal right f access, these refusals shuld be dcumented and included in the inspectin bservatins. At least the fllwing items shuld be reviewed as part f the pharmacvigilance inspectin: Legal and Administrative Aspects Dcumentatin f the respnsible parties fr pharmacvigilance/drug safety activities. Dcumentatin f the selectin and appintment f the registratin/authrizatin hlder s qualified persn fr prduct safety.

5 Recrds f infrmatin n all suspected adverse reactins. Cntracts fr the services utsurced by the registratin/authrizatin hlder. Whether the adverse reactin reprts have been submitted n time, in accrdance with the applicable regulatry prvisins. Preparatin and submissin f annual safety reprts/summary f prduct characteristics (including revisins), clinical trial brchures (including revisins), and peridic safety update reprts, including discussin relating t ff-label use/pediatric use. Cllectin and reprting f serius adverse reactins in clinical trials. Cllectin and reprting f spntaneus adverse reactins. Cllectin, fllw-up and reprting f pregnancy expsure. Cllectin, fllw-up and reprting f the effects n the pediatric ppulatin. Prvisin t the ministry f any ther infrmatin relevant t the evaluatin f the risks and benefits f a medicinal prduct, particularly any infrmatin cncerning pst-authrizatin safety studies (including studies included in risk management plans and pediatric investigatin plans) Organizatinal Structure Quality System and Standard Operating Prcedures (SOP) fr Pharmacvigilance Activities SOPs shuld be dcumented t cver all aspects f pharmacvigilance/drug safety. These SOPs shuld at least include the fllwing: Cllectin and management f all pharmacvigilance data (frm healthcare prfessinals, quality cmplaint departments, regulatry affairs departments, etc.) and f serius adverse reactin data: Causality assessment. Determinatin f seriusness and listedness/expectedness and whether adverse reactins reprts are expedited. Cding. Avidance f duplicate reprting. Ensuring cmpliance with reprting requirements. Identifying and tracking initial and fllw-up reprts. Ensuring an adequate and cmplete fllw-up. Arranging inter-rganizatinal exchange f reprts. Ensuring cmpleteness f the infrmatin cntained in databases. Review, validatin and fllw-up f suspected adverse reactins. Data management (accurate strage and accessibility f infrmatin, tracking f reprts and ensuring timeliness f submissins, cmpliance with cnfidentiality requirements). Expedited reprting t the Ministry, and, where necessary, t all relevant units. Mnitring f wrldwide scientific literature. Cllatin and submissin f peridic safety update reprts/annual safety reprts. Management f requests fr infrmatin by the Ministry. Management f urgent safety restrictins and type II variatins.

6 Updating f cre safety infrmatin/develping safety infrmatin/summary f prduct characteristics (including relevant results f pediatric studies). Signal detectin/trend analysis activities. Management f cmmunicatins with the Ministry as necessary. Creating the risk management plans. Organizatinal charts t identify the key persnnel. Cntrl f all the dcumentatin, including writing, review, apprval, updating, distributin and implementatin f SOPs. Review f quality cntrl prcesses and dcumentatin. Review f crrective and preventive actin prcesses and dcumentatin. Cntrl f the pharmacvigilance system: Determining whether cntrls f pharmacvigilance/drug safety activities have been perfrmed, and identifying the rganizatin wh is in charge f this functins. The prcesses fr cmmunicating and addressing cntrl findings. Cntrls f external institutins/rganizatins, if any, whse services have been hired. Qualificatin and training f cntrllers Qualified Persn fr Prduct Safety Dcumentatin identifying the qualified persn fr prduct safety, alng with qualificatin and training dcumentatin. Dcumentatin f the qualified persn fr prduct safety and cntact details in the quality system Verificatin that the qualified persn fr prduct safety has adequate (direct, timely) access t all relevant pharmacvigilance/drug safety infrmatin. Verificatin that the same qualified persn fr prduct safety has been ntified t all relevant cmpetent authrities. Verificatin that the qualified persn fr prduct safety has sufficient authrity within the cmpany t make amendments t the pharmacvigilance system in rder t ensure cmpliance. Appintment dcumentatin. Dcumentatin that the persn wh deputized fr the qualified persn fr prduct safety in his absence had been appinted as a deputy and s ntified t the Ministry, and verificatin that this prcedure will be applied Resurces and Training f Persnnel Interview f persnnel invlved in any pharmacvigilance activity. Dcumentatin f jb descriptin, qualificatins and training f individuals invlved in any stage f pharmacvigilance/safety evaluatin prcess. Dcumentatin n plicies and prcedures fr training f persnnel. Allcatin f deputies t key persnnel Equipment and Cmputer Systems Cmputer systems in use (administratin, use and hardware/sftware specificatins and validatin apprvals). Migratin f data and legacy system, where relevant. System fr the archiving and retrieval f dcuments.

7 Prcedure fr cllecting, archiving, filing and recvering dcuments. Cntrlled access t the archives Safety Infrmatin frm Clinical Trials Safety infrmatin in cnnectin with clinical trials undertaken by the registratin/authrizatin hlder and matters relating t the harmnizatin f pharmacvigilance databases may be inspected in accrdance with the applicable guidelines Safety Infrmatin frm Other Departments The minimum tpics that shuld be cnsidered when evaluating safety infrmatin received frm ther departments, including quality defects, medicinal r legal infrmatin, are the fllwing: Quality defects and cmplaints shuld be examined t determine whether there are quality defects that culd lead t adverse reactins r whether there may be a quality defect reprted that culd be the cause f actual r ptential adverse reactins and vice versa. Recnciliatin f these data shuld be arranged. Handling f medical infrmatin and legal infrmatin shuld als cnsider detectin f ptential adverse reactins. Infrmatin cllected by marketing and regulatry affairs departments Data/Dcumentatin Review The strategies used during inspectin will depend n the bjective(s) f the inspectin, and the minimum elements that must be cnsidered during review f data/dcuments are prvided belw: Cnfirmatin that ptential adverse reactins frm any surce have been prcessed apprpriately. Determinatin f seriusness. Determinatin f expectedness. Causality assessment. Cnsistency and crrectness f cding with terminlgies used/internal prcedures. Quality and cmpleteness f the medical review. Quality f the infrmatin included in case summaries. Adequacy f fllw-up measures taken. Adequacy f fllw-up infrmatin cllectin and reprting. Any specific questins raised in the inspectin request. Timely submissin f expedited and peridic reprts t authrities. Have all relevant cases (all serius adverse reactins and all nn-serius, unlisted spntaneusly reprted adverse reactins) been examined r included in the line listings f the peridic safety update reprt cvering the relevant time perid? Have qualified, serius reprts frm clinical trials been reprted in an expedited manner and included in peridic safety update reprts and annual safety reprts? Have specific requests in the assessment reprts e.g. fr the presentatin and submissin f data, been apprpriately addressed? Can serius adverse reactins/adverse events be identified in the listings f nnserius adverse reactins/adverse events? Have the results frm literature searches been apprpriately reviewed?

8 Can specific literature cases be accessed in the database? Have new safety issues arising frm pst-apprval studies, cnducted wrldwide, been reprted prmptly t cmpetent authrities? Adequacy f quality cntrl prcess and fllw-up measures taken (crrective actin prcess) Recrding Inspectin Observatins. All inspectin bservatins shuld be dcumented. If pssible, cpies shuld be made f recrds cntaining incnsistencies r illustrating nn-cmpliance. At the end f the inspectin, the inspectrs shuld list and review the nn-cmpliances r system deficiencies. The inspectr(s) shuld ensure that these are dcumented in a clear and cncise manner and are supprted by bjective evidence. All reprted bservatins (findings) shuld be indicated, taking int accunt the specific requirements f the regulatins r ther related dcuments based n which the inspectin has been cnducted. The names and titles f persns interviewed r present during the inspectin meetings and the details f the inspected rganizatin shuld be dcumented Clsing Meeting At the end f the inspectin, the inspectr(s) shuld cnduct a clsing meeting with the inspectee. The qualified persn fr prduct safety, his deputy r ther respnsible persns fr pharmacvigilance activities shuld attend the meeting. The purpse f the clsing meeting is: T summarize inspectin findings and bservatins t ensure that the results f the inspectin are clearly understd and that there is n misunderstanding by either the inspectrs r the inspectees; T prvide the inspectee with an pprtunity t crrect any miscnceptins made by the inspectr r t supply additinal infrmatin in respnse t the findings; T clarify the prcedures fr the distributin f the inspectin reprt, fr the prductin f respnses t the inspectin reprt and fr inspectin fllw-up (as apprpriate); T request cpies f any dcuments that may be required by the inspectr (e.g. t assist with the preparatin fr ther activities assciated with the inspectin). An inspectin may cnsist f visits t mre than ne lcatin. If pssible, a clsing meeting may be held at each lcatin inspected. 6. Preparatin f Inspectin Reprt The lead inspectr, in agreement with ther inspectrs n the team, shall prepare an inspectin reprt in accrdance with the apprpriate guideline. 7. Classificatin f Inspectin Findings 1. Critical: a situatin in pharmacvigilance systems, practices r prcesses that adversely affects the rights, safety r well-being f patients r that pses a ptential risk t public health r that represents a serius vilatin f applicable legislatin. 2. Majr: a situatin in pharmacvigilance systems, practices r prcesses that adversely affects the rights, safety r well-being f patients r that pses a ptential risk t public health r that represents a vilatin f applicable legislatin.

9 3. Minr: a situatin in pharmacvigilance systems, practices r prcesses that wuld nt be expected t adversely affect the rights, safety r well-being f patients. 8. Fllw-up f Inspectin Findings Where an inspectin reveals nn-cmpliances, the registratin/authrizatin hlder will be required t prepare an actin plan, cntaining slutin prpsals t crrect the nn-cmpliances and t avid their recurrence. The registratin/authrizatin hlder may be required t prvide reprt(s), cntaining evidence f the prgress and cmpletin f the actin plan. There may be a fllw-up inspectin at an apprpriate time t verify the prgress and success f the actin plan cntaining the slutin prpsals. 9. Regulatry Actin and Sanctins In the event f nn-cmpliances revealed during an inspectin, the regulatry actin that may be taken include: Educatin and facilitatins: The registratin/authrizatin hlder is infrmed f the nn-cmpliance and advised n hw this can be remedied. Inspectin: Nn-cmpliant registratin/authrizatin hlders may be re-inspected t determine whether the nn-cmpliance has been remedied. Warning: The Ministry may issue a frmal warning t the registratin/authrizatin hlder, reminding him f his pharmacvigilance regulatry bligatins. Naming registratin/authrizatin hlders: The Ministry may make public a list f registratin/authrizatin hlders wh are seriusly r persistently nn-cmpliant. Urgent safety restrictin: The Ministry will act in accrdance with the applicable legislatin. Variatin f Registratin: The Ministry will act in accrdance with the applicable legislatin. Suspensin f Registratin: The Ministry will act in accrdance with the applicable legislatin. Revcatin f Registratin: The Ministry will act in accrdance with the applicable legislatin.

10 Appendix 1: Pharmacvigilance System Overview 1. Cntact Details 1.1. Registratin/Authrizatin Hlder s Name Address Telephne numbers Netwrk address 1.2. Qualified Persn fr Prduct Safety Name and ther functins Address f place f wrk 1.3. Lcatin where pharmacvigilance activities are cnducted 1.4. Number f prducts registered/authrized, number f registratins/authrizatins held in the cuntry 2. Cmpany Organizatin and Pharmacvigilance Mdel 2.1. Brief cmpany prfile including the fllwing: Cmpany s affiliates/wrldwide lcatins. A list f prducts in which the cmpany is specialized and its therapeutic area(s) (prducts registered/authrized and prducts fr which a registratin/authrizatin applicatin has been submitted). Cnslidatins r mergers in recent years (and their impact n and relevance t pharmacvigilance) An verview f the cnduct f pharmacvigilance activities within the cmpany. 3. Pharmacvigilance System 3.1. An verview f the pharmacvigilance activities cnducted at the pharmacvigilance units in Turkey and wrldwide, if any. This sectin shuld be cmpleted by prviding an verview f cmpliance with applicable Regulatins and Guidelines, and shuld incrprate the fllwing sectins: An verview f pharmacvigilance activities cnducted by ther units with verlapping pharmacvigilance functins (e.g., medical, regulatry affairs, r quality cntrl departments). Handling f spntaneus adverse reactin reprting (review f data starting frm the time f receipt, and expedited reprting. Flw diagrams may be used.) A detailed descriptin f the cmpliance mnitring activities perfrmed. Hw are the Peridic Safety Update Reprts (PSURs) and Natinal Reprts prepared, and what is their submissin prcedure t the Ministry? A list f rutine functins f the qualified persn fr prduct safety. A descriptin f the signal generatin and summary f prduct characteristics (SmPC) mdificatin prcedures. Risk management plans (RMP) (Is there an RMP that the cmpany has fr any f its prducts?) 4. Cmputerized Systems fr Pharmacvigilance 4.1. A detailed descriptin f the data prcessing systems/databases used t cllect, cmpare, and evaluate suspected adverse reactins (e.g., spntaneus reprts) A detailed descriptin f the cmputerized systems used in the cuntry t cllect/mnitr adverse reactin reprts, including databases used fr medical infrmatin cnsultancy (diagrams may be used t illustrate the interactin between the systems) A summary f the databases used t cllect, cmpare, and evaluate suspected adverse reactins reprted in the past five years (if any).

11 5. Quality Cntrl System 5.1. Is it the cmpany s intentin t maintain the pharmacvigilance system intact during the six mnths after cmpletin f the PSO? If nt, a summary f the planned mdificatins shuld be prvided Wh is respnsible fr examining the cmpany s pharmacvigilance system? Fr hw lng and where are the examinatin reprts kept? 6. Training Recrds 6.1. A descriptin f the training recrd system, including jb descriptin, bigraphies, and training recrds f key pharmacvigilance persnnel. 7. Archiving 7.1. A brief descriptin f the archiving activities f pharmacvigilance dcuments If a service prvider has been retained n cntract t safeguard the pharmacvigilance dcuments, the name and address f the archive lcatin. 8. Any questins and/r remarks relating t the infrmatin submitted by the cmpany and/r requested by the Ministry 9. Appendices 9.1. All appendices shuld be enumerated Each page shuld have a header/fter cntaining the cmpany name, the number and title f the appendix, and the page number If appendices cannt be prepared, the reasn(s) therefr shuld be described under item The fllwing aspects shuld be appended t the PSO as a supplement: Key Persnnel The names and titles f persns assigned t pharmacvigilance functins in Turkey, and the rganizatinal chart Updated bigraphies and jb descriptins f the qualified persn fr prduct safety and his deputy The names and titles f persns respnsible fr prviding medical infrmatin, r f persns t whm these functins have been delegated, and their rganizatinal charts All Cmpany Prducts A list f all f the cmpany s prducts which are registered/authrized in Turkey (the active substance(s), whether it is marketed in the cuntry, and its cmmercial name in Turkey shuld be indicated fr individual prducts) The tp five prducts in respect f which the highest number f adverse reactins have been reprted during the year preceding the cmpletin f the PSO Quality Cntrl System Standard perating prcedures f pharmacvigilance and ther relevant units (e.g., medical, regulatry affairs, r quality cntrl departments) in matters related t pharmacvigilance Reprting t the Ministry and Statistics Whether the expedited reprting requirements have been met fr spntaneus reprts received by the Ministry The fllwing data fr each mnth frm the past tw years shuld be submitted: Ttal number f serius and nn-serius adverse reactin reprts by the cmpany. Ttal number f adverse reactin reprts submitted t the Ministry accrding t the expedited prcedure. Ttal number f reprts submitted late t the Ministry. Rati f number f cases reprted late t the ttal number f reprts submitted.

12 Cmpliance with the PSUR/NR submissin deadlines which must be submitted after sixty days frm the data-lck pint The fllwing data shuld be submitted fr the PSURs/NRs submitted t the Ministry in the past tw years: Prduct name. Data-lck pint. Date f submissin t the Ministry (if n PSURs have been submitted t the Ministry in the past tw years, data frm the past five years shuld be entered, rdered by date) Third Party Agreements (e.g., with service prviders rendering medical infrmatin r pharmacvigilance services) Any details regarding utsurcing f any functin r activity, directly r indirectly related t pharmacvigilance, within the cuntry t a party ther than the registratin/authrizatin hlder Prduct Safety Issues A list f the prducts withdrawn wrldwide fr safety cncerns during the past five years (date, cuntry where withdrawn, reasn) Details f urgent safety restrictins implemented in the past tw years by the registratin/authrizatin hlder r by cmpetent authrities Other Dcuments in cnnectin with the fllwing activities shuld be submitted: Prcessing f spntaneus adverse reactin reprts. Fllw-up f individual cases. Expedited reprting prcedure t the Ministry. Mnitring cmpliance with the 15-day perids. Preparatin and submissin f PSURs/natinal reprts. Signal analysis. Respnding t medical inquiries.