Guidance On The Format Of The Risk Management Plan (RMP .
31 October 2018EMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Human Medicines EvaluationGuidance on the format of the risk management plan(RMP) in the EU – in integrated formatGeneral consideration and guidanceThis guidance should be read in conjunction with GVP module V.According to GVP module V, the aim of a risk management plan (RMP) is to document the riskmanagement system considered necessary to identify, characterise and minimise the important risks ofa medicinal product. To this end, the RMP contains: the identification or characterisation of the safety profile of the medicinal product, withemphasis on important identified and important potential risks and missing information, andalso on which safety concerns need to be managed proactively or further studied (the ‘safetyspecification’); the planning of pharmacovigilance activities to characterise and quantify clinically relevantrisks and to identify new adverse reactions (the ‘pharmacovigilance plan’); the planning and implementation of risk minimisation measures, including the evaluation of theeffectiveness of these activities (the ‘risk minimisation plan’).Throughout this document, please be as concise as possible and ensure the content is scientificallybased and that it does not include any element of a promotional nature. Consider which informationwill add value to the readers’ understanding of the safety profile of the medicinal product and how bestto interpret and manage the important identified and potential risks as well as the uncertaintiessurrounding the information available. Please focus the document accordingly. Tabulation of any datais encouraged if it aids the presentation.The applicant/marketing authorisation holder should include links or references to the relevant part ofthe eCTD dossier of the supporting documents or PSURs, when applicable. Throughout the RMPtemplate, eCTD data/submissions should be read as eCTD or CTD data/submission, corresponding tothe type of submission to the competent authority. Specific requirements for different types of initialmarketing authorisation applications are described within each section of the template.The examples provided in each Module/Section represent only guidance for writing the RMP and shouldnot be regarded as directions in a defined scenario. Each RMP should be based on the safety data ofthe medicinal product.30 Churchill Place Canary Wharf London E14 5EU United KingdomTelephone 44 (0)20 3660 6000 Facsimile 44 (0)20 3660 5555Send a question via our website www.ema.europa.eu/contactAn agency of the European Union European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged.
Checklist for writing or assessing an RMPThe following general points need to be considered when writing or reviewing an RMP for a medicinalproduct. The checklist is meant to provide further guidance and is not part of the RMP; therefore, itshould not be included in the documents submitted for assessment:Part II: Safety specification Have all appropriate parts of the safety specification been included? Have all appropriate data been reviewed when compiling the safety specification, e.g. are thereimportant (outstanding) issues which have not been discussed in the safety specification? If parts of the target population have not been studied, have appropriate safety concerns inrelation to potential risks and missing information been included? Have limitations in the safety database (e.g. related to the size of the study population, studyinclusion and exclusion criteria) been considered and what are the implications of such limitationson the safety profile of the medicinal product? Has reference been made to populations likely to beexposed during the intended or expected use of the medicinal product in the medical practice?Does the safety specification provide a true reflection of the safety concerns (e.g. importantidentified risks, important potential risks and/or missing information) with the medicinal product? For generic or hybrid applications, have all safety concerns from the latest version of the RMP forthe reference medicinal product or from a list of safety concerns published on the CMDh websitebeen included in the safety specification? If not, has appropriate justification been provided andhas the applicant proposed a list of safety concerns? If no information on the safety profile of thereference medicinal product is available (no RMP or no CMDh list for the substance), has thesafety profile been drafted considering all available relevant information (e.g. public assessmentdocuments for the reference medicinal product, literature, applicant’s own trial data)?Part III: Pharmacovigilance plan Are all safety concerns from the safety specification covered in the pharmacovigilance plan? Are routine pharmacovigilance activities adequate or are additional pharmacovigilance activitiesnecessary? Are the activities in the pharmacovigilance plan clearly defined, described and suitable foridentifying or characterising risks or providing missing information? Are the safety studies that have been imposed by a competent authority as conditions clearlyidentified? If there are safety concerns derived from medication errors, does the RMP include appropriateproposals to monitor the correct use of the product? Are the proposed additional studies necessary, feasible, non-promotional and able to provide therequired further characterisation of the risk(s) and address the scientific questions? Are timelines and milestones appropriate and feasible for the proposed actions, including those forthe submission of results?Part IV: Plans for post-authorisation efficacy studiesGuidance on the format of the risk management plan (RMP) in the EU – in integratedformatEMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Page 2/51
Have all post-authorisation safety studies (PAES), either as conditions of the marketingauthorisation or as specific obligations, been included?Part V: Risk minimisation measures Are routine risk minimisation measures sufficient or is there a need identified for additional riskminimisation activities? Have additional risk minimisation activities been suggested and, if so, are these sufficientlyjustified and risk-proportionate? Is implementation feasible in all Member States? Have criteria for effectiveness of additional risk minimisation activities been defined a priori? Are the methods for evaluating the effectiveness of risk minimisation activities well described andappropriate?Part VI: Summary of the risk management plan Is it a true representation of the RMP? Have the facts been presented appropriately without any elements of promotional nature?Guidance on the format of the risk management plan (RMP) in the EU – in integratedformatEMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Page 3/51
EU Risk Management Plan for Invented name (INN or common name)RMP version to be assessed as part of this application:RMP Version number: Insert number An RMP should be assigned a new RMP version number and a date each time the RMP is updated andsubmitted for assessment (e.g. versions 0.1, 0.2, 0.3 etc. for an initial submission of an RMP; versions1.1, 1.2, etc. and 2.1, 2.2 etc. for RMP updates post-authorisation).The version number of the RMP version agreed at the time of the competent authority opinion shouldbe the same as the one provided with the last eCTD submission in the procedure (most often with theclosing sequence). It is advisable to use major version numbers for final approved RMP versions (e.g.version 1.0 at the end of the initial marketing authorisation application; 2.0, 3.0, etc. for postauthorisation updates).Data lock point for this RMP: Enter a date It is recommended that the Data Lock Point (DLP) should not be more than 6 months before the RMPsign-off date.For initial marketing authorisation applications it usually reflects the DLP of the Clinical SafetySummary.Date of final sign-off: Enter a date The date of sign-off is the date when the draft RMP was considered finalised and ready for submissionto the regulatory agency.Rationale for submitting an updated RMP: Not applicable for initial marketing authorisationapplication submission Summary of significant changes in this RMP: Add high level description of major changes to eachmodule Other RMP versions under evaluation: This section is applicable for post-authorisation RMP updates when a different RMP version is still underassessment with another procedure.If two or more parallel procedures contain RMP submissions, to facilitate assessment, it is usuallyadvised to submit a common consolidated version of the RMP; the supporting Word version of the RMPincluded with the submission should include track changes (colour coded for each procedure), so thatchanges related to each procedure can be easily identified. This will also facilitate the finalisation of theRMP for each procedure.Where the submission of a common, consolidated RMP version is not practical, distinct RMP documentsmay be submitted with each procedure (Word versions should also include tracked changes, perprocedure). For further guidance please refer to European Medicines Agency post-authorisationprocedural advice for users of the centralised procedure 1. The best regulatory path for the RMP update1available on EMA website http://www.ema.europa.euGuidance on the format of the risk management plan (RMP) in the EU – in integratedformatEMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Page 4/51
in case of multiple procedures potentially impacting on the RMP content should be discussed with thecompetent authority before submissions.RMP Version number: Insert number Submitted on: Enter a date Procedure number: indicate procedure number , Details of the currently approved RMP: This section is not required for initial marketingauthorisation applications.There can only be ONE currently approved RMP for a product(s).If several updates to the RMP are submitted during the course of a procedure, the version consideredas the “current” approved RMP for future updates and track-changes purposes shall be the onementioned in the Opinion documents (most often same version is submitted with the closing sequenceof the procedure).Version number: enter a version number Approved with procedure: enter a procedure number Date of approval (opinion date): dd/mm/yyyy QPPV name 2:The QPPV s actual signature or the evidence that the RMP was reviewed and approved by the QPPVshould be included in the finalised approved version of RMP.In the case the option of oversight declaration has been selected and no signature has been submitted,the MAH should have the actual signature in their system, either in pen on paper, digital signatureattached to the RMP document or any other electronic system of document management. For eCTDsubmission, this would be the RMP with the last eCTD sequence of the procedure (usually the closingsequence).Select one of the options:QPPV signature:OrQPPV oversight declaration: The content of this RMP has been reviewed and approved by themarketing authorisation holder s applicant s QPPV. The electronic signature is available onfile. 2QPPV name will not be redacted in case of an access to documents request; see HMA/EMA Guidance document on theidentification of commercially confidential information and personal data within the structure of the marketing-authorisationapplication; available on EMA website http://www.ema.europa.euGuidance on the format of the risk management plan (RMP) in the EU – in integratedformatEMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Page 5/51
Table of contentTable of content . 6Part I: Product(s) Overview . 8Part II: Module SI - Epidemiology of the indication(s) and targetpopulation(s) . 10Part II: Module SII - Non-clinical part of the safety specification. 12Part II: Module SIII - Clinical trial exposure . 13Part II: Module SIV - Populations not studied in clinical trials . 15SIV.1Exclusion criteria in pivotal clinical studies within the development programme . 16SIV.2Limitations to detect adverse reactions in clinical trial development programmes . 16SIV.3 Limitations in respect to populations typically under-represented in clinical trialdevelopment programmes . 16Part II: Module SV - Post-authorisation experience . 17SV.1 Post-authorisation exposure . 18Part II: Module SVI - Additional EU requirements for the safetyspecification . 19Part II: Module SVII - Identified and potential risks . 19SVII.1Identification of safety concerns in the initial RMP submission . 21SVII.2New safety concerns and reclassification with a submission of an updated RMP . 26SVII.3 Details of important identified risks, important potential risks, and missinginformation . 27Part II: Module SVIII - Summary of the safety concerns . 28Part III: Pharmacovigilance Plan (including post-authorisation safetystudies) . 29III.1Routine pharmacovigilance activities . 29III.2Additional pharmacovigilance activities . 30III.3Summary Table of additional Pharmacovigilance activities . 31Part IV: Plans for post-authorisation efficacy studies . 33Part V: Risk minimisation measures (including evaluation of theeffectiveness of risk minimisation activities) . 34V.1. Routine Risk Minimisation Measures. 35V.2. Additional Risk Minimisation Measures . 36V.3Summary of risk minimisation measures . 38Part VI: Summary of the risk management plan . 40II.A List of important risks and missing information. 42II.B Summary of important risks . 43II.C Post-authorisation development plan . 44II.C.1 Studies which are conditions of the marketing authorisation. 44II.C.2 Other studies in post-authorisation development plan . 44Guidance on the format of the risk management plan (RMP) in the EU – in integratedformatEMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Page 6/51
Part VII: Annexes . 45Annex 1 – EudraVigilance Interface . 45Annex 2 – Tabulated summary of planned, ongoing, and completed pharmacovigilance studyprogramme . 45Annex 3 - Protocols for proposed, on-going and completed studies in the pharmacovigilanceplan . 46Annex 4 - Specific adverse drug reaction follow-up forms . 47Annex 5 - Protocols for proposed and on-going studies in RMP part IV . 47Annex 6 - Details of proposed additional risk minimisation activities (if applicable). 47Annex 7 - Other supporting data (including referenced material) . 51Annex 8 – Summary of changes to the risk management plan over time . 51Guidance on the format of the risk management plan (RMP) in the EU – in integratedformatEMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Page 7/51
Part I: Product(s) OverviewTable Part I.1 – Product(s) OverviewUnless significantly different for each product, the following table is expected to be completed onlyonce for each substance.Active substance(s)(INN or common name)Pharmacotherapeuticgroup(s) (ATC Code)Marketing AuthorisationName of the marketing authorisation applicant for initial marketing Holder Applicant authorisation applications.For mutual recognition/ decentralised procedures applicationsinclude also information on expected future marketing authorisationholders in the reference member state, if this information is knownat the time of the application.Medicinal products to whichthis RMP refersIndicate total number of products to which the RMP refers # Invented name(s) in theFor decentralised/mutual recognition products include only theEuropean Economic Areainvented name(s) in the reference member state.(EEA)Marketing authorisation centralised mutual recognition decentralised national procedureBrief description of theproductChemical classSummary of mode of actionImportant information about its composition (e.g. origin of activesubstance for biologicals, relevant adjuvants or residues forvaccines)Hyperlink to the ProductInformationInclude a link or reference to the proposed PI in the eCTD sequence.If no updated PI is submitted with the procedure, the link shoulddirect to the latest approved PI.Indication(s) in the EEACurrent:For initial marketing authorisation applications, this section refers tothe indication proposed by the applicant. For post-authorisationprocedures, it refers to the indication that is currently approved.Proposed (if applicable):For post-authorisation procedures, e.g. if the RMP is submitted withan extension/restriction of indicationGuidance on the format of the risk management plan (RMP) in the EU – in integratedformatEMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Page 8/51
Dosage in the EEACurrent:For initial marketing authorisation applications, this section refers tothe posology proposed by the applicant. For post-authorisationprocedures, it refers to the posology currently approved.Summarise information only related to the main population; not aduplication of all dosages/dosage adjustments for the subpopulations listed in SmPC section 4.2.Proposed (if applicable):Summarise information only related to the main population; not aduplication of all dosages/dosage adjustments for the subpopulations listed in SmPC section 4.2.Pharmaceutical form(s) andCurrent (if applicable):strengthsProposed (if applicable):Is/will the product besubject to additionalmonitoring in the EU?Yes/NoAt initial marketing authorisation application conclusion or with RMPupdatesPart II: Safety specificationFor full initial marketing authorisation applications, all modules in Part II should be submitted. Therequirements for other types of initial marketing authorisation applications are provided in sectionV.C.1.1 of the GVP – Module V.If a reference medicinal product is authorised, please check if it has an RMP/summary for the RMP3published on the EMA and/or national competent authorities’ website or whether the safety concernsfor a substance/reference product are published on the CMDh website. If the Applicant considers that4the available evidence justifies the reclassification or removal of a safety concern, this should bediscussed. Similarly, if the Applicant has identified a new safety concern specific to the product (e.g.risks associated with a new formulation, route of administration or new excipient; or a new safetyconcern raised from any clinical data generated), this should be also discussed and the new safetyconcern detailed in Module SVII.Article 14(2) of Regulation (EC) No 1394/2007 provides for a specific framework for RMP for advancedtherapy medicinal products (ATMP). The marketing authorisation applicants/holders should adapt therisk management plans of ATMP, considering and discussing the anticipated post-authorisation followup needs, focusing on particularities of these medicinal products. The specific RMP contentrequirements for ATMP should be discussed with the competent authority before the p?curl pages/medicines/landing/epar search.jsp&mid ce on the format of the risk management plan (RMP) in the EU – in integratedformatEMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Page 9/51
Part II: Module SI - Epidemiology of the indication(s) andtarget population(s)This section should only contain data relevant for the identification of the safety concerns (see moduleSVII).Information on inter-regional (e.g. EU, US, Asia, Africa etc.) variations may be provided when relevant,but the focus should be on the European population. A brief summary of epidemiology is expected tobe provided. This summary should provide an interpretive, high level overview of the informationavoiding detailed discussion on specific epidemiology studies or published articles.When the medicinal product has/is expected to have several authorised indications, the data for thedifferent indications should be integrated where this is sensible from a clinical perspective. When thereare clinically relevant differences in user characteristics between the authorised indications, separatesections are, however, expected for each authorised indication (e.g. Crohn’s disease and rheumatoidarthritis; multiple sclerosis and hairy cell leukaemia).This module may not be applicable or have a reduced content for RMPs submitted with initial marketingauthorisation applications involving:oGeneric medicinal products;oFixed combination medicinal products which do not contain a new active substance;o“Well established medicinal use” medicinal products;oBiosimilar medicinal products.For hybrid medicinal products, the requirements are based on risk proportionality principle, addressingthe differences with the “originator” product. Indication Incidence:Prevalence:Demographics of the population in the authorised proposed indication – age, gender, racialand/or ethnic origin (when relevant for assessment of safety and risk management) and risk factorsfor the disease:The main existing treatment options: summarise the standard of care, with the view of the expectedsafety profile and outcome in the absence of treatment with the medicinal productNatural history of the indicated condition in the untreated population, including mortality andmorbidity:Discuss the possible stages of disease progression to be treated and applied to the natural history ofthe indication in the (untreated) population. This section should also describe concisely the relevantadverse events to be anticipated in the (untreated) targeted population in EU, their frequency and theircharacteristics.Important co-morbidities:Guidance on the format of the risk management plan (RMP) in the EU – in integratedformatEMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Page 10/51
The risks of the medicinal product are evaluated based on the characteristics of the medicinal product(e.g. documented in clinical trials) and the context of use: expected co-morbidities and co-medicationsin the target population.This section should include, where clinically relevant, diseases distinct from the indication that occurfrequently in patients with the indicated condition (e.g. hypertension is a co-morbidity forhyperlipidaemia); a simple list is sufficient.For guidance on when information should be provided on co-morbidities in the target population,please consider the following examples: If the target population for a medicinal product is men with prostate cancer, the targetpopulation is likely to be men over the age of 50 years, and they have an increased risk formyocardial infarction. Patients with psoriasis are at an increased risk of depression and suicidal ideation andbehaviour.Guidance on the format of the risk management plan (RMP) in the EU – in integratedformatEMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Page 11/51
Part II: Module SII - Non-clinical part of the safetyspecificationThis module should present a high-level summary of the significant non-clinical safety findings. Thetopics should normally include, but do not need to be limited to:Key safety findings from non-clinical studies and relevance to human usage: (for each safety finding)Toxicity key issues identified from acute or repeat-dose toxicity studies reproductive/developmental toxicity genotoxicity carcinogenicitySafety pharmacology as applicable cardiovascular system, including potential effect on the QT interval nervous system etc.Other toxicity-related information or data as applicableWhat constitutes an important non-clinical safety finding will depend upon the medicinal product, thetarget population and experience with other similar compounds or therapies in the same class.Normally, significant areas of toxicity (by target organ system) and the relevance of the findings to theuse in humans should be discussed. Also, quality aspects, if relevant to safety (e.g. genotoxicimpurities), should be discussed. If a medicinal product is intended for use in women of childbearingage, data on the reproductive/developmental toxicity should be explicitly mentioned and theimplications for use in this population should be discussed. Based on these discussions, the applicantshould comment if there are any findings in the non-clinical testing warrant inclusion among thesummary of safety concerns; i.e. being an important identified risk, important potential risk, or if anon-clinical study is missing information.Where studies do not raise concerns in relation to human safety, these should be mentioned, ifrelevant, to the target population (e.g. no signs of reproductive or developmental toxicity if themedicinal product is intended for use in women of childbearing age).For full initial marketing authorisation applications where the Applicant generated no non-clinical data,relevant data available from bibliographical sources should be presented.Where the non-clinical safety finding is not considered relevant for human beings, the provision of abrief explanation is required, and the safety finding is not expected to be carried forward to SVII andSVIII as a risk.If, based on the assessment of the non-clinical or clinical data, additional non-clinical studies areconsidered warranted, this should be briefly discussed here.In the Post-authorisation phase, this section would only be expected to be updated when new nonclinical data impact the list of safety concerns. Safety concerns identified on the basis of non-clinicaldata which are no longer relevant and/or have not been confirmed when sufficient relevant postmarketing experience and evidence are gathered can be removed from the list of safety concerns.Guidance on the format of the risk management plan (RMP) in the EU – in integratedformatEMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2Page 12/51
This module may not be applicable or have a reduced content for RMPs submitted with initial marketingauthorisation applications involving:oGeneric medicinal products;oHybrid medicinal products;o“Well established medicinal use” medicinal products.For fixed combination medicinal products with a new active substance, the focus of this module shouldbe on the data generated for the new active substance. For fixed combination medicinal products withno new active substance, the module should contain information on the new non-clinical datagenerated, if any.Part II: Module SIII - Clinical trial exposureIn this module, in order to assess the limitations of the human safety database, summary informationon the clinical trial exposure should be provided in an appropriate format (e.g. tables/graphs) at timeof submission of the initial RMP or when there is a major update due to new exposure data from clinicalstudies (e.g. in a new indication). The content of this section should be assessed for relevance overtime and, in the absence of new significant clinical trial exposure data, this section does not need to beupdated.Data should be pooled and not shown per individual trial unless there are clearly relevant and dulyjustified reasons why some data cannot be pooled or combined.If the RMP includes more than one medicinal product, the total population table should be provided foreach medicinal product as well as a table that combines the information on total patients exposed forall medicinal products, as appropriate.The cumulative exposure data in this module (including cumulative data per indication, treatmentduration, patient population, formulation), when presented in an aggregated form, would not bedeemed to be commercially confidential and thus would not be redacted in case of an access todocument request (unless a detailed justification is provided which demonstrate how the release of thedata would undermine the commercial interests or competitive position of the company) 5.The categories below are suggestions; tables/graphs should be tai
Guidance on the format of the risk management plan (RMP) in the EU – in integrated format EMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2 Page 4/51 . EU Risk Management Plan for Invented name (INN or common name) RMP version to be assessed as part of th
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