The Egyptian Pharmacovigilance Center (EPVC) http://epvc.gov.eg / Egyptian Guideline for Marketing Authorization Holders (MAHs)Guidelines on Pharmacovigilance for Medicinal Products for Human Use Version 01/ January 2012 The Egyptian Pharmacovigilance Center (EPVC) 1 Version 01 January 2012 Egyptian GuidelineOn Pharmacovigilancefor Medicinal Products for Human Use -Guideline for Marketing Authorization Holders- Version 01 /January 2012 Published: January 2012 Effective: July 2012 The Egyptian Pharmacovigilance Center (EPVC) 2 Version 01 January 2012 PharmacovigilancehasbeendefinedbytheWorldHealthOrganizationasthe scienceandactivitiesrelatingtothedetection,assessment,understandingand prevention of adverse effects or any other medicine-related problem. This Guideline oftheEgyptianPharmacovigilanceCenter(EPVC)hasbeendevelopedtobring guidance on the requirements, procedures, roles and activities in the field of human Pharmacovigilance,forMarketingAuthorizationHolders(MAHs)ofmedicinal products for human use. This guidance describes the respective obligations of the MAH to set up a system for Pharmacovigilanceinordertocollect,collateandevaluateinformationabout suspectedadversereactions.Allrelevantinformationshouldbesharedbetween EPVCandtheMAH,inordertoallowallpartiesinvolvedinpharmacovigilance activities to assume their obligations and responsibilities.Theregulatoryrequirementsstatedinthisguidelinearebasedmainlyonthe EuropeanMedicineEvaluationAgency(EMEA)guidelines(Volume9A)and International Conference for Harmonization (ICH).The ultimate goal is to ensure that the MAHs are fulfilling their principal role in the safety monitoring of their medical products for human use, hence enhance efforts in ensuringthatsafe,efficacious,andqualitymedicinesaremadeavailableforall Egyptians. Itshouldbenoted,aswithallguidancedocumentsinrapidlyevolvingtechnical areas, that this guidance is intended to be regularly reviewed and updated. Edited by: Clinical Pharmacist / Hadir M. Ahmed Team leader of The Egyptian Pharmacovigilance center Rapporteur of Pharmacovigilance Committee Revised by: Dr / Amr A. Saad Head of The Egyptian Pharmacovigilance center The Egyptian Pharmacovigilance Center (EPVC) 3 Version 01 January 2012 Table of contents Table of contents ............................................................................................................................................ 3 Introduction ................................................................................................................................................. 12 1.Legal Basis and Framework for Pharmacovigilance .......................................................................... 12 2.Roles & Responsibilities of Various Parties ......................................................................................... 12 2.1.EPVC ................................................................................................................................................ 12 2.2.The Marketing Authorization Holder (MAH) .................................................................................. 13 2.3.The Pharmacovigilance Committee.................................................................................................. 13 PART I ......................................................................................................................................................... 14 Guidelines for Marketing Authorization Holders .................................................................................... 14 1.Requirements for Qualified Person for Pharmacovigilance (QPPV) ................................................ 15 1.1.Appointment of the Qualified Person for Pharmacovigilance (QPPV)/LSR ................................... 15 1.2.Notification of details of the Qualified Person for Pharmacovigilance ............................................ 16 1.3.Qualifications of a Qualified Person for Pharmacovigilance and Local Safety Responsible ........... 17 1.4.Responsibilities of the Qualified Person for Pharmacovigilance ..................................................... 17 1.4.1.Overview of the pharmacovigilance system ............................................................................... 18 1.4.2.Preparation of reports .................................................................................................................. 20 1.4.3.Answers requests from EPVC ..................................................................................................... 21 1.4.4.Ongoing safety monitoring (post authorization) ......................................................................... 22 1.4.5.Provide input into Risk Management Plans ................................................................................ 23 1.4.6.Contact point for pharmacovigilance inspections ....................................................................... 23 1.5.Responsibilities of the MAH in Relation to the QPPV/LSR ............................................................ 24 1.6.Contractual Arrangements ................................................................................................................ 24 1.7.Special consideration for Multinational MAH/Applicant ................................................................ 25 2.Requirements for Pharmacovigilance Systems, Monitoring of Compliance and Pharmacovigilance Inspections .............................................................................................................................................. 26 2.1.DetailedDescriptionofthePharmacovigilanceSystem(DDPS)tobeincludedintheMarketing Authorization Application ................................................................................................................ 26 2.1.1.Location of the description in the MAA ..................................................................................... 26 2.1.2.Elements of the Pharmacovigilance system that should be described in the Marketing Authorization Application. .......................................................................................................... 26 The Egyptian Pharmacovigilance Center (EPVC) 4 Version 01 January 2012 2.1.2.a.Statement of the MAH and the qualified person regarding their availability and the means for the notification of adverse reactions .................................................................................................... 27 2.1.2.b.Qualified Person Responsible for Pharmacovigilance ................................................................... 27 2.1.2.c.Organization................................................................................................................................... 28 2.1.2.d.Documented Procedures in place, which are documented in writing ............................................ 28 2.1.2.e.Databases ....................................................................................................................................... 31 2.1.2.f.ContractualArrangementswithOtherPersonsorOrganizationsInvolvedintheFulfillmentof Pharmacovigilance Obligations ..................................................................................................... 31 2.1.2.g.Training .......................................................................................................................................... 32 2.1.2.h.Documentation ............................................................................................................................... 32 2.1.2.i.Quality Management system.......................................................................................................... 32 2.1.2.j.Supporting Documentation ............................................................................................................ 32 2.1.3.Special consideration for multinational MAH/Applicant, elements of Egypts office DDPS (local DDPS) ......................................................................................................................................... 33 2.1.3.a.Statement of the MAH and the qualified person/LSR regarding their availability and the means for the notification of adverse reactions .............................................................................................. 33 2.1.3.b.QPPV/LSR located in Egypt .......................................................................................................... 33 2.1.3.c.Organization................................................................................................................................... 34 2.1.3.d.Documented Procedures in place, which are documented in writing ............................................ 35 2.1.3.e.Databases ....................................................................................................................................... 37 2.1.3.f.ContractualArrangementswithOtherPersonsorOrganizationsInvolvedintheFulfillmentof Pharmacovigilance Obligations ..................................................................................................... 37 2.1.3.g.Training .......................................................................................................................................... 37 2.1.3.h.Documentation ............................................................................................................................... 38 2.1.3.i.Quality Management system.......................................................................................................... 38 2.1.3.j.Supporting Documentation ............................................................................................................ 38 2.2.Monitoring of Compliance by EPVC ............................................................................................... 38 2.2.1.QPPV ........................................................................................................................................... 39 2.2.2.Availability of Pharmacovigilance Data ..................................................................................... 39 2.2.3.Change in the Evaluation of the Risk-Benefit Balance of a Product........................................... 39 2.2.4.Expedited Adverse Reaction Reporting ...................................................................................... 39 2.2.5.Periodic Safety Update Reports (PSURs) ................................................................................... 40 2.2.6.Information Requested by EPVC ................................................................................................ 41 The Egyptian Pharmacovigilance Center (EPVC) 5 Version 01 January 2012 2.2.7.Submission of Safety Variations ................................................................................................. 41 2.2.8.Submission of follow-up measures ............................................................................................. 41 2.2.9.Post-Authorization Safety Studies............................................................................................... 42 2.2.10.Provision of Additional Data on Studies ..................................................................................... 42 2.3.Pharmacovigilance Inspections ........................................................................................................ 42 2.3.1.Conduct of Inspections ................................................................................................................ 42 2.3.2.Routine Inspections ..................................................................................................................... 43 2.3.3.Targeted Inspections ................................................................................................................... 43 2.3.4.Pharmacovigilance System Inspections ...................................................................................... 44 2.3.5.Product-Specific Inspections ....................................................................................................... 44 2.3.6.Requesting and Reporting of Inspections .................................................................................... 44 2.3.7.Inspections of Contractors and Licensing Partners ..................................................................... 44 2.3.8.Inspections outside Egypt ............................................................................................................ 45 2.3.9.Fees for Inspections Requested by EPVC ................................................................................... 45 2.3.10.Procedures for Pharmacovigilance Inspections ........................................................................... 45 2.3.11.Unannounced Inspections ........................................................................................................... 45 2.3.12.Inspection Reports ....................................................................................................................... 45 2.3.13.Follow-up of Inspection Findings ............................................................................................... 45 2.4.Regulatory Action ............................................................................................................................ 45 3.Requirements for Risk Management Systems ..................................................................................... 47 3.1.Introduction ...................................................................................................................................... 47 3.2.Description of the Risk Management System .................................................................................. 49 3.3.Egypt Risk Management Plan (EG-RMP)........................................................................................ 49 3.4.Situations Requiring an EG-RMP .................................................................................................... 50 3.5.Location in the Application .............................................................................................................. 51 3.6.Safety Specification .......................................................................................................................... 51 3.6.1.Non-clinical Part of the Safety Specification .............................................................................. 51 3.6.2.Clinical Part of the Safety Specification ..................................................................................... 52 3.6.2.a.Limitations of the Human Safety Database ................................................................................... 52 3.6.2.b.Populations Not Studied in the Pre-Authorization Phase .............................................................. 52 3.6.2.c.Adverse Events/Adverse Reactions ............................................................................................... 53 3.6.2.d.Identified and Potential Interactions including Food-Drug and Drug-Drug .................................. 55 The Egyptian Pharmacovigilance Center (EPVC) 6 Version 01 January 2012 3.6.2.e.Epidemiology ................................................................................................................................. 55 3.6.2.f.Pharmacological Class Effects ....................................................................................................... 55 3.6.2.g.Additional EPVC Requirements .................................................................................................... 56 3.6.3.Summary ..................................................................................................................................... 56 3.7.Pharmacovigilance Plan ................................................................................................................... 57 3.7.1.Routine Pharmacovigilance ......................................................................................................... 57 3.7.2.Additional Pharmacovigilance Activities and Action Plans ....................................................... 57 3.7.3.Action Plan for Safety Concerns ................................................................................................. 58 3.8.Evaluation of the Need for Risk Minimization Activities ................................................................ 58 3.8.1.Potential for Medication Errors ................................................................................................... 59 3.9.The Risk Minimization Plan ............................................................................................................. 60 3.10.Risk Minimization Activities ........................................................................................................... 60 3.10.1.Risk Communication ................................................................................................................... 61 3.11.The Marketing Authorization ........................................................................................................... 61 3.12.Ensuring the Effectiveness of Risk Minimization Activities ........................................................... 61 3.12.1.Assessment of Risk Minimization ............................................................................................... 62 3.13.Summary of Activities in the EG-RMP ............................................................................................ 62 3.14.Submission of Updated EG-RMP Documents ................................................................................. 63 3.15.SpecialconsiderationforMedicinalproductsofMultinationalMAH/Applicant:EgyptianDisplay of the RMP ....................................................................................................................................... 64 3.15.1.Official statement ........................................................................................................................ 65 3.15.2.Summary of Risks ....................................................................................................................... 65 3.15.3.Summary of Activities and action plans ...................................................................................... 65 3.16.Examples of RMP non-compliance .................................................................................................. 66 Table I.3.A: Methods for Risk Minimization ................................................................................................ 68 4.Requirements for Reporting of Individual Case Safety Reports (ICSRs) ........................................ 72 4.1.Introduction ...................................................................................................................................... 72 4.2.Requirements for Expedited Reporting of Individual Case Safety Reports (ICSRs) ....................... 73 4.2.1.Reporting Time Frames ............................................................................................................... 75 4.2.2.Requirements by Reporting Source ............................................................................................. 76 4.2.2.a.Spontaneous Reports from Healthcare Professionals .................................................................... 76 4.2.2.b.Reports Published in the Worldwide Literature ............................................................................. 77 The Egyptian Pharmacovigilance Center (EPVC) 7 Version 01 January 2012 4.2.2.c.Information on Adverse Reactions from the Internet .................................................................... 78 4.2.2.d.Reports from Organized Data Collection Systems ........................................................................ 78 4.2.2.e.Reports from Patients and Other Consumers ................................................................................. 79 4.2.2.f.Reports from Other Non-Medical Sources .................................................................................... 80 4.2.3.Data Elements for the Report ...................................................................................................... 80 4.2.4.Method of Reporting ................................................................................................................... 81 4.3.Requirements for Reporting in Special Situations ........................................................................... 81 4.3.1.Reporting in the Period between the Submission of the Marketing Authorization Application and the Granting of the Marketing Authorization .............................................................................. 82 4.3.2.Reporting Following Suspension or Withdrawal of the Marketing Authorization for Safety or Commercial Reasons ................................................................................................................... 82 4.3.3.Reporting of Outcomes of Use of a Medicinal Product During Pregnancy ................................ 82 4.3.4.Reporting of Adverse Reactions during Breastfeeding ............................................................... 83 4.3.5.Reporting of Data on Use of Medicinal Products in Children .................................................... 83 4.3.6.Reporting from Compassionate/Named-Patient Use................................................................... 84 4.3.7.Reporting of Lack of Efficacy ..................................................................................................... 84 4.3.8.Reporting of Suspected Transmission of Infectious Agents ....................................................... 84 4.3.9.Reporting in Relation to Overdose, Abuse and Misuse .............................................................. 85 4.3.10.Reporting of Medication Errors .................................................................................................. 86 4.3.11.Reporting in the Event of a Public Health Emergency ................................................................ 86 5.Requirements for Periodic Safety Update Reports ............................................................................. 87 5.1.Introduction ...................................................................................................................................... 87 5.2.General Principles ............................................................................................................................ 88 5.2.1.General Scope of Information ..................................................................................................... 88 5.2.2.One Periodic Safety Update Report for Products Containing an Active Substance Authorized to One MAH .................................................................................................................................... 88 5.2.3.Products Authorized to More Than One MAH ........................................................................... 89 5.2.4.Frequency of Review and Reporting ........................................................................................... 90 5.2.4.a.Regular and Ad Hoc Submission of Periodic Safety Update Reports ........................................... 90 5.2.4.b.Submission of Periodic Safety Update Reports for Renewal of Marketing Authorizations .......... 91 5.2.4.c.Circumstances Where the Periodicity May Be Amended .............................................................. 92 5.2.4.d.Preparation of Periodic Safety Update Report according to the International Birth Dates............ 93 5.2.5.Reference Safety Information ..................................................................................................... 93 The Egyptian Pharmacovigilance Center (EPVC) 8 Version 01 January 2012 5.2.6.Presentation of Data on Individual Cases .................................................................................... 95 5.2.6.a.Sources of Information .................................................................................................................. 95 5.2.6.b.Description of the Adverse Reaction ............................................................................................. 95 5.2.6.c.Line listings and/or Summary Tabulations .................................................................................... 96 5.3.Model for a Periodic Safety Update Report (PSUR) ........................................................................ 98 5.3.1.PSUR section Executive Summary .......................................................................................... 98 5.3.2.PSUR section Introduction ...................................................................................................... 98 5.3.3.PSUR section Worldwide Marketing Authorization Status ..................................................... 99 5.3.4.PSUR section Update of Regulatory Authority or Marketing Authorization Holder Actions taken for Safety Reasons ......................................................................................................... 100 5.3.5.PSUR section Changes to Reference Safety Information ...................................................... 100 5.3.6.PSUR section Patient Exposure ............................................................................................. 101 5.3.6.a.Exposure in clinical trials............................................................................................................. 101 5.3.6.b.Market experience ........................................................................................................................ 101 5.3.7.PSUR section Presentation of Individual Case Histories ...................................................... 102 5.3.7.a.Cases Presented as Line-Listings ............................................................................................. 103 5.3.7.b.Cases Presented as Summary Tabulations ............................................................................... 104 5.3.7.c.MAHs Analysis of Individual Case Histories ......................................................................... 105 5.3.8.PSUR section Studies ............................................................................................................ 105 5.3.8.a.Newly Analyzed Studies .......................................................................................................... 105 5.3.8.b.Targeted New Safety Studies ................................................................................................... 106 5.3.8.c.Published Studies ..................................................................................................................... 106 5.3.8.d.Other Studies ............................................................................................................................ 106 5.3.9.PSUR section Other information ........................................................................................... 106 5.3.9.a.Efficacy-related Information .................................................................................................... 106 5.3.9.b.Late-breaking Information ....................................................................................................... 106 5.3.9.c.Risk Management Plan ............................................................................................................. 107 5.3.9.d.Risk-Benefit Analysis Report ................................................................................................... 107 5.3.10.PSUR section Overall Safety Evaluation ............................................................................... 107 5.3.11.PSUR section Conclusion ...................................................................................................... 108 5.4.Contents of the PSUR Summary Bridging Report ......................................................................... 108 5.5.Contents of the PSUR Addendum Report ...................................................................................... 109 The Egyptian Pharmacovigilance Center (EPVC) 9 Version 01 January 2012 5.6.Examples of PSUR non-compliance .............................................................................................. 110 6.Company-Sponsored Post-Authorization Safety Studies ................................................................. 112 6.1.Introduction .................................................................................................................................... 112 6.2.Objectives of Post-Authorization Safety Studies ........................................................................... 113 6.3.Responsibilities for the Conduct of Post-Authorization Safety Studies ......................................... 114 6.4.Liaison EPVC ................................................................................................................................. 114 6.4.1.Evaluation of the Protocol ......................................................................................................... 114 6.4.2.Reporting of Adverse Reactions ................................................................................................ 115 6.4.3.Progress and Final Study Reports ............................................................................................. 116 6.5.Promotion of Medicinal Products ................................................................................................... 116 6.6.Participation of Healthcare Professionals ....................................................................................... 117 6.7.Ethical Issues .................................................................................................................................. 117 6.8.Procedure for Complaints ............................................................................................................... 117 TABLE I.6.A: Epidemiological methods for post-authorization safety studies .......................................... 118 TABLE I.6.B: Elements to be considered in the protocol of post-authorization safety Studies as appropriate ..................................................................................................................................................... 124 TABLE I.6.C: Elements to be considered in the final study report............................................................. 127 7.Overall Pharmacovigilance Evaluation and Safety-Related Regulatory Action ............................ 128 7.1.Introduction .................................................................................................................................... 128 7.2.Signal Detection and Evaluation .................................................................................................... 128 7.3.Principles of Risk-Benefit Assessment........................................................................................... 129 7.3.1.Assessment of Benefits ............................................................................................................. 129 7.3.2.Assessment of Risks .................................................................................................................. 130 7.3.3.Risk-Benefit Assessment ........................................................................................................... 130 7.4.Improving the Risk-Benefit Balance .............................................................................................. 131 7.5.Withdrawal of a Product from the Market on Risk-Benefit Grounds ............................................ 132 7.6.Communication .............................................................................................................................. 132 PART II ...................................................................................................................................................... 133 GuidelinesforMarketingAuthorizationHoldersandtheEgyptianPharmacovigilanceCenter (EPVC) Communication ........................................................................................................................... 133 1.Direct Healthcare Professional Communications ............................................................................. 134 The Egyptian Pharmacovigilance Center (EPVC) 10 Version 01 January 2012 1.1.Introduction .................................................................................................................................... 134 1.2.Definition of Direct Healthcare Professional Communication ....................................................... 134 1.3.Key Principles for Public Communication on Medicinal Products ................................................ 134 1.4.Situations Where a Direct Healthcare Professional Communication Should Be Considered ........ 135 1.5.Key Principles for Preparation of Texts for Direct Healthcare Professional Communications ..... 136 1.6.The Processing of Direct Healthcare Professional Communications ............................................. 137 1.6.1.The Roles and Responsibilities of MAHs and EPVC ............................................................... 137 1.6.2.Phased Approach to Processing ................................................................................................ 137 1.6.3.Translations ............................................................................................................................... 140 ANNEXES .................................................................................................................................................. 141 1.Glossary ................................................................................................................................................. 142 1.1.General ........................................................................................................................................... 142 1.2.Terms in Relation to Risk Management ......................................................................................... 147 2.Abbreviations........................................................................................................................................ 149 3.Other Guidelines and Relevant Terminology .................................................................................... 151 3.1.Other Pharmacovigilance Guidelines ............................................................................................. 151 3.1.1.Note for Guidance on the Electronic Data Interchange (EDI) of Individual Case Safety Reports (ICSRs) and Medicinal Product Reports (MPRs) in Pharmacovigilance During the Pre- and Post- Authorization Phase in the European Economic Area (EEA) ................................................... 151 3.1.2.Guideline on the Exposure to Medicinal Products During Pregnancy: Need for Post-Authorization Data .................................................................................................................... 151 3.1.3.Guideline on the Conduct of Pharmacovigilance for Medicines Used by the Paediatric Population.................................................................................................................................. 151 3.2.Relevant Terminology .................................................................................................................... 151 3.2.1.Medical Terms ........................................................................................................................... 151 3.2.2.Standard Terms on Pharmaceutical Dosage Forms, Routes of Administration and Containers 151 3.2.3.Controlled Vocabulary for Routes of Administration ............................................................... 151 3.2.4.Controlled Vocabulary for Units and Measurements ................................................................ 151 4.ICH Guidelines ..................................................................................................................................... 152 4.1.ICH-E2B(M) - Maintenance of the Clinical Safety Data Management Including: Data Elements for Transmission of Individual Case Safety Reports ........................................................................... 152 4.1.1.ICH- E2B Q&As (R5): Questions and Answers Data Elements for Transmission of Individual Case Safety Reports ........................................................................................................................... 152 The Egyptian Pharmacovigilance Center (EPVC) 11 Version 01 January 2012 4.2.ICH-E2C(R1):ClinicalSafetyDataManagementPeriodicSafetyUpdateReportsforMarketed Drugs including Addendum to ICH-E2C ....................................................................................... 152 4.3.ICH-E2D:Post-ApprovalSafetyDataManagement-DefinitionsandStandardsforExpedited Reporting ........................................................................................................................................ 152 4.4.ICH-E2E: Pharmacovigilance Planning ......................................................................................... 152 4.5.ICH-M1: Medical Terminology - Medical Dictionary for Regulatory Activities (MedDRA) ....... 152 4.6.ICH-M2:ElectronicStandardsforTransmissionofRegulatoryInformation(ESTRI)-Individual Case Safety Report (ICSR) ............................................................................................................. 153 4.7.ICH-M5: Data Elements and Standards for Drug Dictionaries ...................................................... 153 4.7.1.Routes of Administration Controlled Vocabulary ..................................................................... 153 4.7.2.Units and Measurements Controlled Vocabulary ..................................................................... 153 4.8.ICH-E2A:ClinicalSafetyDataManagement-DefinitionsandStandardsForExpeditedReporting ........................................................................................................................................................ 153 5.Templates .............................................................................................................................................. 154 5.1.1.Template for Egyptian Risk Management Plan (EG RMP) ................................................... 155 5.1.2.Template for PSUR ................................................................................................................... 175 5.1.3.Template for Direct Healthcare Professional Communications (DHPCs) ................................ 188 6.Classification of Batch Recalls for Quality Defects ........................................................................... 190 References .................................................................................................................................................. 191 The Egyptian Pharmacovigilance Center (EPVC) 12 Version 01 January 2012 Introduction 1.Legal Basis and Framework for Pharmacovigilance PharmacovigilancehasbeendefinedbytheWorldHealthOrganizationasthescienceand activities relating to the detection, assessment, understanding and prevention of adverse effects or anyothermedicine-relatedproblem.ThelegalframeworkforPharmacovigilanceof pharmaceutical products for human use in Egypt is given in the Ministerial Decree No. (397/1995) concerningtheestablishmentofNationalPharmacovigilanceCenter,MinisterialDecreeNo. (632/2010) concerning the establishment of Pharmacovigilance Committee and Assistant Minister ofHealthdecreeNo.(2/2010)concerningtheregulationsofPharmacovigilanceand Pharmaceuticalproductssafety.BeingpartoftheEgyptianDrugAuthorityEPVC recommendationandpharmacovigilanceassessmentsareinvolvedintheregulatoryprocessof other EDA departments, this considered as indirect legal framework. ThelegislationlistedaboveandthisguidelinedescribetherespectiveobligationsoftheMAH (MAH)andofEgyptianPharmacovigilanceCenter(EPVC)tosetupasystemfor Pharmacovigilanceinordertocollect,collateandevaluateinformationaboutsuspectedadverse reactions.AllrelevantinformationshouldbesharedbetweenEPVCandtheMAH,inorderto allowallpartiesinvolvedinpharmacovigilanceactivitiestoassumetheirobligationsand responsibilities. This requires an intensive exchange of information between the MAH and EPVC aswellasprocedurestoavoidduplication,maintainconfidentialityandensurethequalityofthe systems and data. TherequirementsexplainedintheseguidelinesarebasedontheInternationalConferencefor Harmonization(ICH)andtheEuropeanMedicineEvaluationAgency(EMEA)guidelines,where these exist, but may befurther specified or contain additional requests in line with the legislation of EPVC. Pharmacovigilance activities come within the scope of the criteria of quality, safety and efficacy, as new information is accumulated on the medicinal product under normal conditions of useinthemarketingsituation.Pharmacovigilanceobligationsapplytoallauthorizedmedicinal products in Egypt. Thisguidanceisrequiredtoincludetechnicalrequirementsfortheelectronicexchangeof pharmacovigilance information in accordance with internationally agreed formats. 2.Roles & Responsibilities of Various Parties 2.1.EPVC Inaccordancewiththelegislation,EPVChasestablishedapharmacovigilancesystemforthe collection and evaluation of information relevant to the risk-benefit balance of medicinal products. The Egyptian Pharmacovigilance Center (EPVC) 13 Version 01 January 2012 EPVCcontinuallymonitorsthesafetyprofileoftheproductsavailableinEgyptandtakes appropriateactionwherenecessaryandmonitorsthecomplianceofMAHswiththeirobligations with respect to pharmacovigilance. EPVC should ensure that MAHs implement, when appropriate, Risk Management Plans to effectively monitor and manage risks associated with the safety of their products. 2.2.The Marketing Authorization Holder (MAH) The MAH ensure that it has an appropriate system of pharmacovigilance and risk management in place in order to assure responsibility and liability for its products on the market and to ensure that appropriate action can be taken, when necessary. The roles and responsibilities of the MAH include but not limited to the following: 1.Establish and maintain a system to collect, collate, and evaluate pharmacovigilance data. 2.Meet legal obligations for reporting of suspected adverse reactions. 3.Meet legal obligations regarding the preparation and the submission of periodic Safety Update Reports. 4.RespondfullytorequestsfromEPVCforadditionalinformationnecessaryfortheevaluation of the benefits and risks of a medicinal product. 5.Ensure the marketing authorization is maintained and reflects the latest information. 2.3.The Pharmacovigilance Committee TheroleofthePharmacovigilanceadvisorycommitteeistoprovideadviceonthesafetyof medicinalproductsandtheinvestigationofadversereactions,inordertoenableeffectiverisk identification,assessmentandmanagement,inthepre-andpost-authorizationphase(seechapter I.3) leading to recommendations on action at the request of EPVC for products available in Egypt. TherolesandresponsibilitiesofthePharmacovigilanceAdvisoryCommitteeincludebutnot limited to the following: 1.Evaluationofpotentialsignalsarisingfromspontaneousreporting,includingthoseidentified from national database for adverse drug reactions, and all other sources. 2.Investigation of adverse reactions. 3.Regularly review Drug monitor of safety concerns. 4.Discussion of emerging safety concerns at the request of EPVC 5.Discussion of PSURs at the request of the EPVC. 6.Recommendations to EPVC on Risk-benefit evaluations and actions necessary to minimize risk and maximize benefit. 7.ProvidingadvicetoEPVConsafety,enablingeffectiveriskidentification,assessmentand management in the pre- and post-authorization phase. The Egyptian Pharmacovigilance Center (EPVC) 14 Version 01 January 2012 PART I Guidelines for Marketing Authorization Holders The Egyptian Pharmacovigilance Center (EPVC) 15 Version 01 January 2012 1.Requirements for Qualified Person for Pharmacovigilance (QPPV) The MAH should ensure that it has an appropriate system of pharmacovigilance in place in order to assume responsibility and liability for its products on the market and to ensure that appropriate actionmaybetakenwhennecessary.TheMAHshouldthereforeensurethatallinformation relevant to the risk-benefit balance of a medicinal product is reported to EPVC fully and promptly in accordance with the legislation. When submitting an application for a marketing authorization, the Applicant, in preparation for the roleandresponsibilitiesasMAH,shouldsubmitadescriptionofthepharmacovigilancesystem andsubmitproofthattheservicesofaQualifiedPersonResponsibleforPharmacovigilance, hereafter referred to as the QPPV, are in place (see chapter I, 2). TheMAHshouldhavepermanentlyandcontinuouslyathisdisposalaQPPV,residinginEgypt. FormultinationalMAH;iftheQPPVisnotresidinginEgypt(regionalQPPVorHeadquarter QPPV);thentheMAHshouldhaveinadditiontothatQPPVaLocalSafetyResponsible(LSR) residing in Egypt. This LSR should be physician or pharmacist experienced or adequately trained in Pharmacovigilance as detailed in Chapter I.1, section 3).Eachcompany(i.e.Applicant/MAHorgroupofMAHsusingacommonpharmacovigilance system)shouldappointoneQPPVresponsibleforoverallpharmacovigilanceforallmedicinal products for which the company holds marketing authorizations within Egypt.TheQPPV/LSRshouldbeappropriatelyqualified,withdocumentedexperience/traininginall aspects of pharmacovigilance in order to fulfill the responsibilities and tasks of the post. Thenameand24-hourcontactdetailsoftheQPPV/LSRandback-upprocedurestoensure business continuity and continued fulfillment of pharmacovigilance obligations should be notified to the EPVC. 1.1.Appointment of the Qualified Person for Pharmacovigilance (QPPV)/LSR MedicinalproductscannotbemarketedwithinEgyptwithoutaQualifiedPersonfor Pharmacovigilance (QPPV) {andLocal Safety Responsible (LSR) if the QPPV is not residing in Egypt (multinational MAH)}. Itistheresponsibilityofthecompany,thatis,Applicant/MAHorgroupofMAHsusinga common pharmacovigilance system, to appoint a QPPV. This should follow the following rules: TheappointmentoftheQPPV(andLSR)shouldbedocumentedinanappropriateway,for example in a job description or written agreement. A signed QPPV (and LSR) statement is also requiredaspartofthecompanysdetaileddescriptionofthepharmacovigilancesystem (DDPS) in marketing authorization applications.Back-uparrangementsshouldbeinplaceforwhenEgyptsQPPV(andLSR)isunavailable, such as another appropriately qualified individual who can assume the role and responsibilities The Egyptian Pharmacovigilance Center (EPVC) 16 Version 01 January 2012 oftheQPPV(andLSR)intheirabsence(whiletheroleitselfcannotbedistributedamonga number of personnel, tasks may be delegated to a variety of individuals).It is acknowledged that small companies may not have sufficient resource available in-house to address the requirements for a QPPV and appropriate back-up arrangements. Therefore, MAH may transfer any or all pharmacovigilance tasks and functions, including the role of the QPPV, toanotherperson(s)ororganization(outsourcing)(thisoutsourcingdoesnotapplyforLSR). Theultimateresponsibilityforthefulfillmentofpharmacovigilancerequirementsalways resides with the MAH, but a contract QPPV also assumes specific legal responsibilities. When a contract QPPV is employed the following should be considered: (i) The MAH is responsible for ensuring that there is a contract in place between the company and the QPPV, which adequately describes the responsibilities of each party and the tasks to be allocated to the QPPV, prior to the QPPV commencing work with the MAH. Details ofthecontractualarrangementsforpharmacovigilanceactivitieshavetobenotifiedto EPVC, for example within the DDPS that is included as part of a marketing authorization application.Thecontractshouldbeappropriatelyamendedorupdatedwhenchangesto contractual arrangements occur. (ii)TheMAH,orpersons(s)appointedbytheMAHforthistask,shouldassessthecontract QPPV(orback-upQPPV)inordertoensurethathe/sheisappropriatelyqualified,has knowledge of the applicable regulatory requirements and has the ability to fulfill the tasks that have been assignedto him/her by the MAH, for example adequate arrangements for 24-hour availability. This assessment should be documented. (iii)ThecontractQPPVwouldbeexpectedtoperformanassessmentoftheMAHs pharmacovigilance system. (iv)TheMAHshouldensurethatthecontractQPPVhassufficientauthoritytoinstigate changestotheMAHspharmacovigilancesysteminordertopromote,maintainand improve compliance with regulatory requirements. (v)ThecontractQPPVshouldimplementappropriatequalityassurance(QA)andquality control(QC)proceduresinrelationtothetasksthattheyhaveagreedtoundertakeon behalf of the MAH. 1.2.Notification of details of the Qualified Person for Pharmacovigilance TheDDPSthatmustbeincludedinapplicationsformarketingauthorizationsshouldcontain information relating to the QPPV (and LSR). IftheMAHchangesitsQPPV/LSR,thesameinformationmustbeprovidedforthenew QPPV/LSR. The MAH should have a mechanism in place for notification of QPPV/LSR changes to EPVC, for example a process for DDPS variations. Even if a MAH with products authorized in The Egyptian Pharmacovigilance Center (EPVC) 17 Version 01 January 2012 EgypthasnotsubmittedaDDPS,theMAHshouldprovideEPVCwithcurrent24-hourcontact details of their QPPV/LSR and details of the back-up arrangements. IfaMAHholdsmarketingauthorizationsbutdoesnotcurrentlymarketanyofthesemedicinal products, the company is still required to have an QPPV (and LSR) in place as pharmacovigilance requirements, for example expedited reporting, Periodic Safety Update Report (PSUR) production and literature searching, still apply. EPVC will maintain a list of QPPVs (and LSRs). This list will include business address and contact details (including out of- business hours contact details).1.3.QualificationsofaQualifiedPersonforPharmacovigilanceandLocalSafety Responsible TheQPPV/LSRshouldresideandperformtheirfunctionsasQPPVinEgypt.Anappropriately qualified person who assumes the role and responsibilities of the QPPV/LSR when the QPPV/LSR is absent (back up person) should also reside in Egypt (when acting as QPPV/LSR).The QPPV/LSR should:Pharmacist or physician Dedicated to his/her job as a QPPV/LSR (full time job) Ideally, the QPPV/LSR should have worked forsomeyears in the field of pharmacovigilance oratleasthavereceivedsuitablepharmacovigilanceformaltraining.Medicallyqualified personswhoprovidepharmacovigilancesupporttotheQPPV/LSRshouldalsohavetraining and experience appropriate to their role and responsibilities.Demonstrate (e.g. through qualifications, work experience and formal training) that he/she has knowledgeofapplicableEgyptianpharmacovigilancelegislationandguidance,international standardsforpharmacovigilance(e.g.InternationalConferenceonHarmonization(ICH)and Council for International Organizations of Medical Sciences (CIOMS) guidance. Demonstrate (e.g. through qualifications, work experience and formal training) that he/she has knowledgeofthekeypharmacovigilanceactivitiesperformedaspartoftheMAHs pharmacovigilance system & how to implement them.The MAH should ensure that the QPPV/LSR has access to a medically qualified person if the QPPV/LSR is not medically qualified (pharmacist). The process that the QPPV/LSR would use toobtainsuchmedicaladviceincludingoutsideofnormalworkinghoursshouldbeclearly documented in a written procedure or agreement.TheMAHshouldprovidecomprehensivetraininginPharmacovigilancetotheQPPV(see Chapter I.2, Section 1.2.b) or LSR (see Chapter I.2, Section 1.3.b). 1.4.Responsibilities of the Qualified Person for Pharmacovigilance TheQualifiedPersonforPharmacovigilance/LSRispersonallyresponsibleinlawforthe fulfillment of 3 key functions: The Egyptian Pharmacovigilance Center (EPVC) 18 Version 01 January 2012 Establish and maintain the Market Authorization Holders (MAH) Pharmacovigilance System (includingallactivitieswhichcontributetothedetection,assessment,understandingand communicationofsafetyinformation,aswellasriskmanagementactivities).Inaddition,the LSRisresponsiblewiththeQPPVformaintainingtheMAHPharmacovigilanceSystemin Egypt.Overseethesafetyprofilesofthecompanysmarketedproductsandanyemergingsafety concerns. Act as a single point of contact for the regulatory Authorities on a 24-hour basis, and provide the contact point for pharmacovigilance inspections. TheQPPV/LSRisresponsibleforaddressingspecificrequirements(aslistedbelow).Itis recognizedthatthisimportantroleoftheQPPV/LSRmayimposeextensivetasksonthe QPPV/LSR,dependingonthesizeandcomplexityofthepharmacovigilancesystemandthe numberandtypeofproductsforwhichthecompanyholdsauthorizations.TheQPPV/LSRmay, therefore,delegatespecifictasks,undersupervision,toappropriatelyqualifiedandtrained individuals(e.g.actingassafetyexpertsforspecificproducts),providedthattheQPPV/LSR maintainsoversightofthesystemandanoverviewofthetasksthathavebeendelegated(the QPPV retains legal responsibility for compliance with these specific requirements). Inordertomeettherequirements,itisessentialthattheMAHensuresthattheQPPV/LSRhas sufficientauthoritytoimplementchangestothepharmacovigilancesysteminordertopromote, maintain and improve compliance. It is expected that the QPPV/LSR will receive adequate support from senior management within the MAH to enable him/her to address his/her responsibilities and to ensure that there are appropriate processes, resources, communication mechanisms and access to allsourcesofrelevantinformationinplaceforthefulfillmentoftheQPPVs/LSRs responsibilities and tasks. Overview of the pharmacovigilance systemPreparation of reports. Answers requests from EPVC. Ongoing safety monitoring. Provide input into Risk Management Plans (RMPs).Contact point for pharmacovigilance inspections. 1.4.1.Overview of the pharmacovigilance system TheQPPV/LSRshallberesponsibleforestablishingandmanaging/maintainingasystemwhich ensuresthatinformationconcerningallsuspectedadversereactionsthatarereportedtothe personnelofthecompanyandtomedicalrepresentativesiscollected,evaluatedandcollatedso that it may be accessed. The QPPVs/LSR oversight should cover the functioning of the MAHs pharmacovigilance system inallrelevantaspects,includingQCandQAprocedures,standardoperatingprocedures(SOPs), The Egyptian Pharmacovigilance Center (EPVC) 19 Version 01 January 2012 databaseoperations,contractualarrangements,compliancedata(e.g.inrelationtothequality, completeness and timeliness for expedited reporting and submission of PSURs), audit reports and training of personnel in relation to pharmacovigilance. Expectations with respect to QPPV/LSR oversight are as follows: (I) STANDARD OPERATING PROCEDURES TheQPPV/LSRshouldhaveanawarenessoftheMAHsproceduresforkeypharmacovigilance activities. As appropriate, the QPPV/LSR may have input into or approvekeywritten procedures inordertoassurecompliancewiththerequirements.Ifthecompanyhasglobalandlocalwritten proceduresforkeypharmacovigilanceactivities,theQPPV/LSRmayneedtohaveanawareness of both types of procedure in order to ensure consistency and compliance across the organization. (II) DATABASES TheQPPV/LSRshouldbeawareofthesystemthatisusedtocollect,evaluateandcollate information concerning all suspected adverse reactions. A computer database is often an essential partofsuchasystem.However,alternativestoacomputerdatabasemaybeacceptableprovided thattheMAHisabletocomplywiththerequirementstosendelectronicreportstoEPVC.Ifa computerdatabaseisusedforcollectionandcollationofadversereactioninformation,the QPPV/LSRshouldbeawareofthevalidationstatusofthedatabase,includinganyfailuresthat occurred during validation and the corrective actions that have been taken to address the failures. TheMAHshouldimplementaproceduretoensurethattheQPPV/LSRisabletoobtain information from the database at any time, for example to respond to requests for information fromEPVC.Ifthisprocedurerequirestheinvolvementofotherpersonnel(e.g.information technology (IT) programmers), then this should be taken into account in the arrangements made by theMAHforsupportingtheQPPV/LSRoutsideofnormalworkinghours.Itmaybeappropriate fortheQPPV/LSRtobenotifiedifsignificantchangestothepharmacovigilancedatabaseare planned, such as being provided with the impact assessment report. (III) QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES TheQPPV/LSRshouldhaveanawarenessoftheQCproceduresthatareusedforkey pharmacovigilanceactivities,forexampleforcaseprocessingandPSURproduction.These proceduresshouldbeadequatelydocumented.TheMAHshouldimplementaperiodicQAaudit programmeforpharmacovigilanceofatypeappropriatetotheMAHssystem.Auditsshould coveralldepartmentsthatmayreceiveadversereactionreportsorthatareinvolvedin pharmacovigilanceactivities(includingdrugsafety,clinicalresearch,productquality,medical information, regulatory affairs, sales and marketing, the legal department) plus affiliate, contractor, co-licensingandco-distributioncompanies,asappropriate.Auditandinspectionreportfindings relatingtopharmacovigilanceshouldbemadeavailabletoappropriateMAHpersonnel,in particular,theQPPV/LSR.TheQPPV/LSRshouldalsobemadeawareofthecorrectiveactions that are taken to address significant audit findings and compliance issues. The Egyptian Pharmacovigilance Center (EPVC) 20 Version 01 January 2012 (IV) COMPLIANCE DATA TheQPPV/LSRhasspecificlegalresponsibilitieswithrespecttothepreparationforEPVCof seriousadversereactionreports,PSURsandPost-authorizationSafetyStudy(PASS)reports;the QPPV/LSR should receive compliance information on a periodic basis to enable him/her to assess the quality, completeness and timeliness of submission of these reports. (V) CONTRACTUAL ARRANGEMENTS Wherepharmacovigilancetaskshavebeentransferredtoanotherpersonororganization,detailed andclearlydocumentedcontractualarrangementsarerequiredthatadequatelydescribethe responsibilitiesofeachpartyandtheinformationtobeexchangedbetweentheparties.The QPPV/LSRshouldhaveanawarenessofthoseagreementsthatincludepharmacovigilancetasks and safety data exchange in order to ensure that the agreements facilitatecompliance with EPVC pharmacovigilance requirements. The MAH should implement mechanisms to facilitate this. When a MAH intends to expand its product portfolio, for example by acquisition of another MAH orbypurchasingindividualproductsfromanotherMAH,itisadvisablethattheQPPV/LSRis notifiedatanearlystageoftheduediligenceprocessinorderthatthepotentialimpactonthe pharmacovigilancesystemcanbeassessed.TheQPPV/LSRmayalsohavearoletoplayin determining what pharmacovigilance data should be requested from the other MAH either pre- or post-acquisition.Inthissituation,itisadvisablefortheQPPV/LSRtobemadeawareofthe sectionsofthecontractualagreementsthatrelatetoresponsibilitiesforpharmacovigilance activities and safety data exchange. (VI) TRAINING TheQPPV/LSRisexpectedtohavereceivedappropriatetraininginrelationtotheMAHs pharmacovigilancesystemandthistrainingshouldbedocumented.TheQPPV/LSRshouldalso haveanawarenessofthesystemfor,andtypeof,pharmacovigilancetrainingprovidedtoother MAHpersonnel.MAHpersonnelshouldbemadeawareoftheidentity,contactdetailsand responsibilities of the QPPV/LSR, asappropriate. Ways in whicha MAH can raise the profile of the QPPV/LSR within an organization include posting details of the QPPV/LSR on the companys intranet,highlightingtheroleoftheQPPV/LSRincompanynewslettersorvisitsbythe QPPV/LARtoaffiliateoffices.Theexpectationslistedabovealsoapplytoanypersonwho assumes the role of the QPPV/LSR, when the QPPV/LSR is unavailable.1.4.2.Preparation of reports TheQPPV/LSRshallberesponsibleforthepreparationforEPVCofIndividualCaseSafety Reports(ICSR)forsuspectedseriousadversereactionandPeriodicSafetyUpdateReports (PSUR), in accordance with applicable legislative requirements and guidance. The Egyptian Pharmacovigilance Center (EPVC) 21 Version 01 January 2012 ItshouldbestressedthatLSRisnotrequiredpersonallytopreparetheabovereports(incaseof multinationalMAHswhereregionalorheadquarterQPPVmaytakeonthisresponsibility). However, the LSR should have an adequate and appropriate overview of the quality, completeness and timeliness of adverse reaction reports and PSURs submitted to EPVC. The QPPV/LSR should have sufficient authority to make changes to the pharmacovigilance system, where appropriate on an international basis, to ensure compliance with reporting obligations. Possible mechanisms by which the QPPV/LSR can obtain an overview of compliance include, but are not limited to: awarenessandinputintotheprocessesandproceduresestablishedbytheMAHforthe preparation and submission of adverse reaction reports and PSURs; awareness and input into the training of key personnel involved in these activities; periodicreceiptandreviewofcompliancedatarelatingtopreparationandsubmissionof adverse reaction reports and PSURs; receipt and review of appropriate QC data and QA audit reports. TheQPPV(butnotLSR)mustprepareandsignthePSUR.TheresponsibleQPPVmaydelegate thepreparationofthePSURtoanappropriatelyqualifiedandtrainedindividual.Thatindividual mayalsosignthePSURprovidedthatthereisaletterofdelegationsignedbytheQPPVand attached to the PSUR cover letter. Such a letter may cover more than one medicinal product and/or more than one PSUR. 1.4.3.Answers requests from EPVC The QPPV/ LSR shall be responsible for ensuring that any request from EPVC for the provision of additionalinformationnecessaryfortheevaluationofthebenefitsandrisksaffordedbya medicinal product is answered fully and promptly, including the provision of information about the volume of sales or prescriptions of the medicinal product concerned. AprocessshouldbeestablishedtoensurethatrequeststotheMAHfromEPVCforthe provisionofinformationnecessaryfortheevaluationofbenefitsandrisksarepromptly communicated to the QPPV/LSR. This process should include affiliate offices, contractors, co-distributionandco-marketingpartners,asappropriate.Althoughthetaskofrespondingto requestsmaybedelegatedtootherpersonnel,theQPPV/LSRislegallyresponsibleforthe completeness,accuracyandpromptnessofresponsestorequestsfromEPVCforinformation necessary for the evaluation of benefits and risks.Any other regulatory requests received and managed by regulatory affairs personnel, but it may be related to the provision of information necessary for the evaluation of benefits and risks, the QPPV/LSRshouldbemadeawareofthisrequestandtheresponse.TheQPPV/LSRshould haveawarenessoftheprocessforproducingtheresponse,shouldreceiveacopyofthe response and, where appropriate, should review and approve the response. The Egyptian Pharmacovigilance Center (EPVC) 22 Version 01 January 2012 The QPPV/LSR should have adequate and appropriate access to safety information, sales data andproductexpertisetoenabletheQPPV/LSRtorespondfullyandpromptlytorequestsfor information from EPVC.TheMAH/QPPVshouldconsiderimplementingasystemtocaptureandtrackrequestsfor informationfromCompetentAuthorities(Egyptian&/orglobalauthorities),andtheinformation provided in response to such requests. The documentation associated with a Competent Authority request and with the MAHs response to the request should be retained. The system implemented may also be used to track specific Competent Authority requests for presentation and discussion of data in PSURs. 1.4.4.Ongoing safety monitoring (post authorization) The QPPV/LSR shall be responsible for the provision to EPVC- in a timely manner- of any safety updates or any other information relevant to the evaluation of the benefits and risks afforded by his medicinalproduct,includingappropriateinformationonpost-authorizationsafetystudies, literaturesafetyinformationandworldwideregulatoryactionsduetosafetyreasons(e.g.label changes, withdrawals, suspensions, recalls..etc.). TheQPPV/LSRshouldhaveoversight,eitherdirectlyorthroughsupervision,oftheconductof continuous overall pharmacovigilance evaluation during the post-authorization period.For this purpose, the QPPV/LSR should have an overview of the safety profiles and any emerging safetyconcernsrelatingtothemedicinalproductsforwhichtheMAHholdsauthorizationsin Egypt. This does not mean that the QPPV/LSR has to be a product safety expert for all products, buttheQPPV/LSRisexpectedtohaveaccesstoappropriateproduct-specificexpertisewhen required.Inadditiontothementionedabovepost-authorizationsafetymonitoringactivities,theQPPVof theMAHforgenericmedicinalproduct,shouldcontinuouslykeepaneyeonanysafetyupdates &/orsafetyregulatoryactionstakenforitsreferencemedicinalproduct(whetherthisreference product is authorized in Egypt or in the reference countries). Some issues that the QPPV/LSR/MAH may want to consider in relation to these points are given below. (i)Mechanisms that have been implemented to keep the QPPV/LSR informed of emerging safety concernsandanyotherinformationrelatingtotheevaluationofthebenefitsrisksbalance. Thisshouldincluderelevantliteratureinformation,relevantinformationfromclinicaltrials (e.g. recommendations from clinical trial safety-monitoring boards that may have implications fortheuseoftheproductinauthorizedindications)and,whererelevanttotheevaluationof benefits and risks, clinical trial Annual Safety Reports (ASRs) and study reports for products authorized in Egypt.(ii)InvolvementoftheQPPV/LSRinorawarenessofsafetycommitteemeetings,where applicable.Ifnot,he/sheshouldreceiveinformationorminutesfromrelevantmeetingsin The Egyptian Pharmacovigilance Center (EPVC) 23 Version 01 January 2012 order to be informed of emerging safety issues and the actions that have been taken to address these issues. (iii)Providing the same information on emerging safety concerns to the person who would act as a back-up when the QPPV/LSR is absent. (iv)TheQPPV/LSRshouldbeinvolvedinthereviewofprotocolsforallPost-Authorization SafetyStudies(PASS)sponsoredbytheMAH(involvingproductsauthorizedinEgypt),in ordertoensurecompliancewithpharmacovigilancerequirementsandthisreviewshouldbe documented. (v)When a PASS is conducted in Egypt, the QPPV/LSR is responsible for providing EPVC with appropriateinformationrelatingtothesestudies.TheQPPV/LSRshouldbemadeawareof the status of the studies and be provided with copies of study reports (interim and final). The QPPV/LSR should be made aware that protocols and reports had been submitted to EPVC to ensurecompliancewiththelegislation.TheQPPV/LSRshouldbeinvolvedindecisionsto provideEPVCwithnewinformationrelevanttotheevaluationofthebenefitsandrisksfor products authorized in Egypt. The QPPV/LSR should approve the submissions that are made. The QPPV/LSR should be informed of the findings and have access to the reports from PASS forproductsauthorizedinEgyptandsponsoredbytheMAH(withinandoutsideEgypt).A safetyconcernmayunexpectedlybeidentifiedduringastudyonamedicinalproduct authorized in Egypt but in a study or clinical trial that is not classified as a PASS. In this case, theMAHandspecificallytheQPPV/LSRareexpectedtoinformEPVCimmediatelyandto provideabriefreportonprogressatintervalsandatstudyendasrequestedbyEPVC.The QPPV/LSRshouldbemadeawareofcommitmentsmadeatthetimeofauthorization (including in Risk Management Plans (RMPs) for provision of additional information relevant totheevaluationofthebenefitsandrisks,andtheQPPV/LSRshouldensurethatthese commitmentsareadequatelyaddressed.Thetasksmaybedelegatedtootherpersonnel,but the QPPV/LSR should have an overview of how the commitments are addressed. The liaison betweenEPVCandtheMAHonpharmacovigilance-relatedissuesshouldtakeplaceviathe QPPV/LSR. 1.4.5.Provide input into Risk Management PlansTheQPPV/LSRshouldhavesufficientauthoritytoprovideinputintoRiskManagementPlans (RMPs) and into the preparation of regulatory action in response to emerging safety concerns, for examplevariations,urgentsafetyrestrictionsand,asappropriate,communicationtopatientsand healthcare professionals (HCPs). 1.4.6.Contact point for pharmacovigilance inspectionsThe QPPV/LSR should also act as the MAHs contact point for pharmacovigilance inspections or shouldbemadeawarebytheMAHofanyinspectionthatmayimpactthepharmacovigilance system, in order to be available as necessary. The Egyptian Pharmacovigilance Center (EPVC) 24 Version 01 January 2012 MAHproceduresshoulddescribethecommunicationprocesstobefollowedwhenaninspection notificationisreceived.TheQPPV/LSRshouldbekeptinformedconcerningtheinspection arrangements.TheMAHshouldensurethattheQPPV/LSRisnotifiedofinspectionfindings relevant to his/ her role and responsibilities. 1.5.Responsibilities of the MAH in Relation to the QPPV/LSR TheMAHshouldadequatelysupporttheQPPV/LSRandensurethatthereareappropriate processes, resources, communication mechanisms and access to all sources of relevant information in place for the fulfillment of the QPPVs/LSRs responsibilities and tasks. The MAH should ensure that there is full documentation covering all procedures and activities of theQPPV/LSRandthatmechanismsareinplacetoensurethattheQPPV/LSRmayreceiveor seek all relevant information. The MAH should also implement mechanisms for the QPPV/LSR to be kept informed of emerging safety concerns and any other information relating to the evaluation oftherisk-benefitbalance.Thisshouldincludeinformationfromongoingorcompletedclinical trialsandotherstudiestheMAHisawareofandwhichmayberelevanttothesafetyofthe medicinalproduct,aswellasinformationfromsourcesotherthanthespecificMAH,e.g.from those with whom the MAH has contractual arrangements. The MAH should ensure that the QPPV/LSR has sufficient authorityto implement changes to the MAHs pharmacovigilance system in order to promote, maintain and improve compliance; and toprovideinputintoRiskManagementPlans(seeChapterI,3)andintothepreparationof regulatoryactioninresponsetoemergingsafetyconcerns(e.g.variations,urgentsafety restrictions, and, as appropriate, communication to Patients and Healthcare Professionals). The MAH should assess risks with potential impact on the pharmacovigilance system and plan for business contingency, including back-up procedures (e.g. in case of non-availability of personnel, adversereactiondatabasefailure,failureofotherhardwareorsoftwarewithimpactonelectronic reporting and data analysis). 1.6.Contractual Arrangements The MAH may transfer any or all of the pharmacovigilance tasks and functions, including the role oftheQPPV,toanotherperson(s)ororganization(PVauthorizedrepresentative),butthe ultimate responsibility for the fulfillment of all pharmacovigilance obligations and the quality and integrity of this always resides with the MAH. In such cases, it is the responsibility of the MAH to ensurethatdetailedandcleardocumentedcontractualarrangementsformeeting pharmacovigilanceobligationsareinplacebetweenMAH(s)andpersonsororganizations involvedinthefulfillmentofpharmacovigilanceobligationsandtoprovideEPVCwith informationonsucharrangementsinlinewiththerequirementssetoutinchapterI.2.The The Egyptian Pharmacovigilance Center (EPVC) 25 Version 01 January 2012 contractedperson(s)ororganizationshouldimplementqualityassuranceandqualitycontroland accept to be audited by or behalf of the MAH. IncasesofcontractualarrangementsbetweenMAHsinrelationtoco-marketingofseparately authorizedmedicinalproductswhichareidenticalinallaspectsapartfromtheirinventednames, these arrangements should include measures to avoid the duplicate submission of Individual Case Safety Reports (e.g. literature reports) to EPVC. 1.7.Special consideration for Multinational MAH/Applicant Multinational MAH/Applicant; if the QPPV is not residing in Egypt (the MAH has regional QPPV orHeadquarterQPPV);thentheMAHshouldhaveinadditiontothatQPPVaLocalSafety Responsible (LSR) residing in Egypt. All the conditions and qualifications stated for QQPV in thischapter(I.1)applyalsoforLSR.LSRwillrepresentasinglepointofcontactwithEPVC. Similar to the QPPV, the LSR should be physician or pharmacist, dedicated to his/her job as LSR (fulltimejob)andexperienced/trainedinPharmacovigilance(seeChapterI.1section3).The ultimategoalistoensurethatEgyptLSRisadequatelyqualifiedinpharmacovigilanceandhas widebackgroundaboutpharmacovigilanceactivitieseventhosenotregularlyperformedbyhim, but he may get involved in them in special situations to fulfill EPVC requirement. Inaddition,theLSRshouldhaveinhis/herabsenceabackuppersonresidinginEgypt(atleast when acting as LSR) The Egyptian Pharmacovigilance Center (EPVC) 26 Version 01 January 2012 2.RequirementsforPharmacovigilanceSystems,Monitoringof Compliance and Pharmacovigilance Inspections ThisChaptersetsouttheframeworkforimplementation,inthecontextoftherevised pharmaceuticallegislation,ofthemonitoringofcompliancewithpharmacovigilanceobligations andofpharmacovigilanceinspections.Inthesamecontextitsetsoutthe requirementforMAH's pharmacovigilancesystemandtheinformationtobesuppliedintheapplicationgivingadetailed description of the pharmacovigilance system of the MAH and proof that the MAH has the services of QPPV and the necessary means for the notification of adverse reactions.2.1.Detailed Description of the Pharmacovigilance System (DDPS) to be included in the Marketing Authorization Application TheApplicantforamarketingauthorizationisrequiredtoprovideadetaileddescriptionofthe systemofpharmacovigilanceand,whereappropriate,oftheriskmanagementsystemwhichthe Applicant will introduce. 2.1.1.Location of the description in the MAAThe detailed description of the pharmacovigilance system, including the proof of the availability of the services of the QPPV and the proof that theMAH has the necessarymeans for the collection andnotificationofanyadversereaction,shouldbeprovidedinModule1/section1.8ofthe application dossier, or whenever requested by EPVC . The detailed description should comprise an overview of the pharmacovigilance system providing informationonthekeyelementsofthatsystem.Whereaspectsofthesystemsuchasthe organizationalarrangementsareparticulartotheproductratherthanthemainsystemofthe MAH/company(MAHoragroupofMAHssharingthesamepharmacovigilancesystem)this should be indicated in a product-specific addendum. The detailed description should be supported by documentation maintained by the company. Updatestotheinformationprovidedinthedetaileddescriptionofthepharmacovigilancesystem should be made as type II variations. 2.1.2. ElementsofthePharmacovigilancesystemthatshouldbedescribedintheMarketing Authorization Application.AllMAHsmusthaveanappropriatesystemofpharmacovigilanceinplace.Thedetailed description of the pharmacovigilance system should include the following elements, as applicable, andbesetoutinastructuredmannerconsistentwiththislist.Additionalimportantelements pertinent to a specific situation should be added: The Egyptian Pharmacovigilance Center (EPVC) 27 Version 01 January 2012 2.1.2.a.StatementoftheMAHandthequalifiedpersonregardingtheiravailabilityand the means for the notification of adverse reactionsThe Applicant should provide a signed statement from the MAH and theQPPV to the effect that the applicant has their services available as QPPV and has the necessarymeans for the collection and notification of any adverse reaction occurring either in Egypt or other country. This statement may make reference to the detailed description of the pharmacovigilance system and indicate what is already in place, and confirm which items will be put in place before the product is placed on the market /registered in Egypt. 2.1.2.b.Qualified Person Responsible for PharmacovigilanceThenameoftheQPPVlocatedinEgypt.Thebusinessaddressandcontactdetailsshouldbe provided in the Marketing Authorization Application form. Companies might, for example, use a24-hourtelephonenumberthroughwhichtheQPPVortheirback-upcanbereached, diverting it to the appropriate person according to availability. Summary Curriculum Vitae of the QPPV with the key information relevant to their role (main qualifications, training and experience). The QPPV training should include (but not limited to): oAdvanced pharmacovigilance oMedDRA coding. oFollow up, validation and assessment of the ICSRs oEvidence based medicine, How to conduct literature search. oCausality assessmentoCase Narrative Writing for Reporting Adverse Events oPharmacovigilance inspection oPharmaco-epidemiology oSignal detection oHow to prepare a PSUR oRisk Benefit assessment in Pharmacovigilance oPharmacovigilance Planning and Risk Management Plans oHow to prepare a DDPS oMedical Aspects of Adverse Drug Reactions In addition, QPPV should be aware of: oEuropean Pharmacovigilance regulations (as the Egyptian PV regulations are based on the European PV regulations) oEgyptian Pharmacovigilance regulation, PSUR, RMP, DDPS, Dear Dr Letter. A summary of the job description of the QPPV. A description of the back-up procedure to apply in the absence of the QPPV. The Egyptian Pharmacovigilance Center (EPVC) 28 Version 01 January 2012 2.1.2.c.OrganizationIdentification and location of the company units or other organizations where the principal and globalpharmacovigilanceactivitiesareundertakeninparticularthosesiteswherethemain databases are located, where Individual Case Safety Reports (ICSRs) are collated and reported andwherePSURs(PeriodicSafetyUpdateReports)areprepared,reviewed(includingwhere medical review takes place) and processed for reporting to EPVC. High-levelorganizationchart(s)providinganoverviewoftheglobalandEgypt pharmacovigilance units and organizations (identified above) and, illustrating the relationships betweenthem,withaffiliate/parentcompaniesandcontractors.Thechart(s)shouldshowthe main reporting relationships with management and clearly show the position of Egypts QPPV withintheorganization.Individualnamesofpeopleshouldnotbeincluded.Linkswithother departmentsinvolvedinpharmacovigilanceactivitiesshouldbeindicated(e.g.regulatory affairs,medicalinformation,salesandmarketing,clinicalresearch,productquality,quality assuranceaudit(forpharmacovigilance),andinformationtechnologysupporting pharmacovigilancedatabase(s).Licensingpartnershipsareusuallyproduct-specificandshould beindicatedinaproduct-specificaddendumintheapplicationforthatproduct,unlessa partnership is a consistent feature of the companys organization across most products. Abriefsummaryofthepharmacovigilanceactivitiesundertakenbyeachofthe organizations/units identified above. Flowdiagramsindicatingtheflowofsafetyreportsofdifferentsourcesandtypes.These shouldindicatehowreports/informationareprocessedandreportedfromthesource,tothe point of receipt by EPVC, where appropriate, to healthcare providers. Abriefdescriptionofarchivingactivitiesforpharmacovigilanceactivities,locationand responsibility for these. Abriefdescriptionoftheresponsibilitiesforqualityassuranceauditingofthecompanys pharmacovigilance systems.2.1.2.d.Documented Procedures in place, which are documented in writingAnessentialelementofanypharmacovigilancesystemistohaveclear,writtenproceduresin place. The following list indicates topics that should be covered by these written procedures. The detailed description should indicate for which of these topics there are written procedures in place, but should not list the procedure titles per se. A procedure may cover one or more of the topics or one topic may have oneor more procedures depending on its complexityand the organization of thecompany.Careshouldbetakentoensurethatqualitycontrolandreviewareappropriately addressed in the various processes and reflected in the relevant procedures The activities of the QPPV and the back-up procedure to apply in their absence; The Egyptian Pharmacovigilance Center (EPVC) 29 Version 01 January 2012 The collection, processing (including data entry and data management), quality control, coding, classification, medical review and reporting of ICSRs. Reports of different types should be addressed: oOrganized data collection schemes (solicited), unsolicited, clinical trials, literature oThe process should ensure that reports from different sources are captured: Egyptandothercountries,healthcareprofessionals,salesandmarketingpersonnel,other MAH personnel, licensing partners,, compassionate use, patients, others; Thefollow-upofreportsformissinginformationandforinformationontheprogressand outcome of the case(s); Detection of duplicate reports; Expedited reporting of individual case safety reports (ICSRs); Electronic reporting of individual case safety reports (ICSRs) Periodic Safety Update Reports (PSURs):The preparation, processing, quality control, review (including medical review) and reporting; Globalpharmacovigilanceactivitiesapplyingtoallproducts:Continuousmonitoringofthe safety profile of authorized medicinal products (product-specific risk management systems and pharmacovigilance planning are covered in (Chapter I,3): oSignal detection and review; oRisk-benefit assessment; oReportingandcommunication notifying EPVCand healthcare professionals ofchanges to the risk-benefit balance of products, etc.; Interaction between safety issues and product defects; Responses to requests for information from regulatory authorities; Handling of urgent safety restrictions and safety variations; Meeting commitments to EPVC in relation to a marketing authorization; Management and use of databases or other recording systems; Internal audit of the pharmacovigilance system; Training; Archiving. Ideally this information can be presented as the following table: The Egyptian Pharmacovigilance Center (EPVC) 30 Version 01 January 2012 Description/ objective of SOP SOP number SOP title The activities of the QPPV and the back-up procedure to apply in their absence; The collection, processing (including data entry and data management), quality control, coding, classification, medical review and reporting of ICSRs. The follow-up of reports for missing information and for information on the progress and outcome of the case(s); Detection of duplicate reports; Expedited reporting of individual case safety reports (ICSRs); Electronic reporting of individual case safety reports (ICSRs) Periodic Safety Update Reports (PSURs): The preparation, processing, quality control, review (including medical review) and reporting Global pharmacovigilance activities, monitoring of safety profile oSignal detection and review; oRisk-benefit assessment; oReporting and communication notifying EPVC and healthcare professionals of changes to the risk-benefit balance of products Interaction between safety issues and product defects; Responses to requests for information from regulatory authorities; Handling of urgent safety restrictions and safety variations; Meeting commitments to EPVC in relation to a marketing authorization; Management and use of databases or other recording systems; Internal audit of the pharmacovigilance system; Training; Archiving The Egyptian Pharmacovigilance Center (EPVC) 31 Version 01 January 2012 Alistandcopiesofthe globalandEgyptianproceduresshouldbeavailablewithinthreedayson requestbyEPVC.Anyadditionallocalproceduresshouldbeavailabletorespondtospecific requests. All information received by the MAH should be managed in order to respect the confidentiality of patients and reporters.2.1.2.e.DatabasesAlistingofthemaindatabasesusedforpharmacovigilancepurposes(e.g.compilationofsafety reports,expedited/electronicreporting,signaldetection,sharingandaccessingglobalsafety information)andbrieffunctionaldescriptionsoftheseshouldbeprovidedincludingastatement regarding the validation status of the database systems. Astatementshouldbeincludedregardingthecomplianceofthesystemswiththeinternationally agreed standards for electronic submission of adverse reaction reports. AcopyoftheregistrationoftheQPPVwiththeEgyptianVigilancesystemandidentificationof the process used for electronic reporting to EPVC. Thereshouldbeanindicationoftheresponsibilityfortheoperationofthedatabasesandtheir location (with reference to the locations identified under Section 1.2.c above organization). 2.1.2.f.ContractualArrangementswithOtherPersonsorOrganizationsInvolvedinthe Fulfillment of Pharmacovigilance Obligations Linkswithotherorganizationssuchasco-marketingagreementsandcontractingof Pharmacovigilanceactivitiesshouldbeoutlined.Thecompanyshouldidentifythemajor subcontracting arrangements it has for the conduct of its pharmacovigilance activities and the main organizationstowhichithassubcontractedthese(inparticularwheretheroleoftheQPPV,the electronic reporting of ICSRs, the main databases, signal detection, or the compilation of PSURs is subcontracted). Abriefdescriptionofthenatureoftheagreementsthecompanyestablisheswithco-marketing partners and contractors for pharmacovigilance activities should be provided.Sinceco-licensingorco-marketingarrangementsaremainlyproduct-specificanyinformationon these may be provided in a product-specific addendum, in the applicable Marketing Authorization Application.Likewiseifsubcontractingisproduct-specificthisshouldbeindicatedinaproduct specific addendum. The Egyptian Pharmacovigilance Center (EPVC) 32 Version 01 January 2012 2.1.2.g.TrainingStaffshouldbeappropriatelytrainedforperformingpharmacovigilancerelatedactivities.This includesnotonlystaffwithinthepharmacovigilanceunitsbutalsostaffwhomayreceiveor process safety reports, such as sales personnel or clinical research staff. Provide a brief description ofthetrainingsystemandindicatewherethetrainingrecords,CurriculaVitae(CVs)andjob descriptions are filed. 2.1.2.h.DocumentationProvideabriefdescriptionofthelocationsofthedifferenttypesofpharmacovigilancesource documents,includingarchivingarrangements.Referencecanbemadetotheorganizationcharts provided under Section 3.2 above (organization). 2.1.2.i.Quality Management systemProvideabriefdescriptionofthequalitymanagementsystem,makingcross-referencetothe elementsprovidedundertheaboveSections.Particularemphasisshouldbeplacedon organizationalrolesandresponsibilitiesfortheactivitiesanddocumentation,qualitycontroland review, and for ensuring corrective and preventive action. A brief description of the responsibilities for quality assurance auditing of the Pharmacovigilance system, including auditing of sub-contractors, should be provided. 2.1.2.j.Supporting Documentation The MAH should ensure that the pharmacovigilance system is in place and documented. An essential feature of a pharmacovigilance system is that it is clearly documented to ensure that the system functions properly, that the roles and responsibilities and required tasks are clear to all partiesinvolvedandthatthereisprovisionforpropercontroland,whenneeded,changeofthe system. Documentationsupportingthepharmacovigilancesystem(anditsdetaileddescription)maybe requiredduringthepre-authorizationperiod,orpost-authorization,forpurposessuchas assessment or inspection. Failuretosubmitthesedetailsinamarketingapplicationmayleadtodelaysinthe processingoftheapplication.Inadequatedetailsmayprovidegroundsforrejectionofthe application.Pharmacovigilanceinspectorswillchecktheconsistencyofthe pharmacovigilancesystemwiththeDDPSsubmittedbytheMAH(andanysubsequent variations) during pharmacovigilance inspections. The Egyptian Pharmacovigilance Center (EPVC) 33 Version 01 January 2012 2.1.3.SpecialconsiderationformultinationalMAH/Applicant,elementsofEgyptsoffice DDPS (local DDPS) AllMAHsmusthaveanappropriatesystemofpharmacovigilanceinplace.Itisunderstoodthat for Multinational MAH/Applicant the Pharmacovigilance system in Egypt functions as a part of its globalpharmacovigilancesystemandintegratewithit.Accordingly,theseMAHs/Applicants should provide clear illustration of the key elements of both global pharmacovigilance system and EgyptPharmacovigilancesystem,highlightingtheroleofEgyptQPPV/LSR,which pharmacovigilanceactivitiesarecarriedoutinEgypt,whicharecarriedoutinthe headquarter/globally and how they integrate together. The DDPS should be submitted in the application dossier or whenever requested by EPVC. For the Multinational MAH/Applicant the following 2 DDPSs are required: 1.Headquarter/global DDPS (according to Volume 9A of the EMEA and as detailed in Chapter I.2) and, 2.EgyptsofficeDDPS(localDDPS)whichdescribesthekeyelementsofPharmacovigilance systeminEgypt:Itshouldincludethefollowingelements,asapplicable,andbesetoutina structured manner consistent with this list. 2.1.3.a.Statement of the MAHand the qualified person/LSR regarding their availability and the means for the notification of adverse reactionsThe Applicant should provide a signed statement from the MAH and the Egypt QPPV/LSR to the effectthattheapplicanthastheirservicesavailableasEgyptQPPV/LSRandhasthenecessary meansforthecollectionandnotificationofanyadversereactionoccurringinEgypt.This statementmaymakereferencetothedetaileddescriptionofthepharmacovigilancesystemand indicate what is already in place, and confirm which items will be put in place before the product is placed on the market /registered in Egypt. 2.1.3.b.QPPV/LSR located in EgyptThe name of the Egypt QPPV/LSR located in Egypt. The business address and contact details shouldbeprovidedintheMarketingAuthorizationApplicationform.Companiesmight,for example, use a 24-hour telephone number through which the Egypt QPPV/LSR or their back-up can be reached, diverting it to the appropriate person according to availability. Summary Curriculum Vitae of the Egypt QPPV/LSR with the key information relevant to their role (main qualifications, training and experience). The Egypt QPPV/L