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Eu module VII: PSUR released for public consultation

Saravanan Subramanian (SAS), profile picture
Saravanan Subramanian (SAS)

This document provides guidance on the preparation, submission, and assessment of periodic safety update reports (PSURs) in the European Union. It describes the objectives, format, and content of PSURs, and provides further details on the submission of PSURs in the EU, including the list of EU reference dates and frequency of submission. It also covers the single EU assessment process for PSURs and quality systems related to PSURs at the level of marketing authorization holders, European Medicines Agency, and competent authorities in EU member states.

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See websites for contact details European Medicines Agency www.ema.europa.eu Heads of Medicines Agencies www.hma.eu The European Medicines Agency is an agency of the European Union © European Medicines Agency and Heads of Medicines Agencies, 2013. Reproduction is authorised provided the source is acknowledged. 19 April 20131 EMA/816292/2011 Rev 1*2 Guideline on good pharmacovigilance practices (GVP)3 Module VII – Periodic safety update report (Rev 1)4 Date for coming into effect of first version 2 July 2012 Draft Revision 1* finalised by the Agency in collaboration with Member States 21 March 2013 Draft Revision 1 agreed by ERMS FG 27 March 2013 Draft Revision 1 adopted by Executive Director 19 April 2013 Released for public consultation 25 April 2013 End of consultation (deadline for comments) 25 June 2013 Revised draft Revision 1 finalised by the Agency in collaboration with Member States Revised draft Revision 1 agreed by ERMS FG Revised draft Revision 1 adopted by Executive Director as final Date for coming into effect of Revision 1 Q 4 2013 5 *Note: Revision 1 contains the following:6 - Updates in VII.B and VII.C.5. following finalisation of the ICH-E2C(R2) guideline on “Periodic Benefit-7 Risk Evaluation Report (PBRER)”, which reached Step 4 of the ICH process in November 2012, in order8 to harmonise the principles and agreements reached by the ICH Expert Working Group;9 - Further guidance regarding technical aspects on the implementation of Regulation (EU) No10 1235/2010 and Directive 2010/84/EU based on the experience gained since July 2012;11 - Practical instructions for the application, description and maintenance of the EU reference date list in12 VII.C.3.2., VII.C.3.3. and VII.C.3.4. and amendments to the marketing authorisation in VII.C.3.7.;13 - Further instructions regarding the PSUR assessment process, product information and transitional14 arrangements within the EU regulatory network in VII.C..15 16 Comments should be provided using this template. The completed comments form should be sent to
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 2/69 gvp@ema.europa.eu. 17 Note for public consultation:18 The public consultation is restricted to the yellow highlighted revised texts (i.e. replaced by new texts19 with deletions and additions) or deleted texts (i.e. not replaced). However, if revisions or deletions20 impact or contradict other existing text, comments on such non-highlighted texts will be processed and21 taken into account for the finalisation process. Please note that ICH-E2C(R2) guideline has already22 been subject to public consultation in the EU, and participants in the consultation process are therefore23 asked not to comment on the underlying agreements reached at ICH level.24 25 26
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 3/69 TABLE OF CONTENTS27 VII.A. Introduction...................................................................................... 628 VII.B. Structures and processes .................................................................. 729 VII.B.1. Objectives of the periodic update safety report (PSUR) ........................................730 VII.B.2. Principles for the evaluation of the risk-benefit balance within PSURs and scope of31 the information to be included ......................................................................................832 VII.B.3. Principles for the preparation of PSURs ..............................................................933 VII.B.4. Reference information .....................................................................................934 VII.B.5. Format and contents of the PSUR....................................................................1135 VII.B.5.1. PSUR section “Introduction” ........................................................................1436 VII.B.5.2. PSUR section “Worldwide marketing authorisation status" ...............................1437 VII.B.5.3. PSUR section “Actions taken in the reporting interval for safety reasons” ..........1538 VII.B.5.4. PSUR section “Changes to reference safety information” .................................1639 VII.B.5.5. PSUR section “Estimated exposure and use patterns” .....................................1640 VII.B.5.5.1. PSUR sub-section “Cumulative subject exposure in clinical trials” ..................1641 VII.B.5.5.2. PSUR sub-section “Cumulative and interval patient exposure from marketing42 experience”..............................................................................................................1743 VII.B.5.6. PSUR section “Data in summary tabulations” .................................................1844 VII.B.5.6.1. PSUR sub-section “Reference information”..................................................1845 VII.B.5.6.2. PSUR sub-section “Cumulative summary tabulations of serious adverse events46 from clinical trials” ....................................................................................................1947 VII.B.5.6.3. PSUR sub-section “Cumulative and interval summary tabulations from post-48 marketing data sources” ............................................................................................1949 VII.B.5.7. PSUR section “Summaries of significant findings from clinical trials during the50 reporting interval”.....................................................................................................2051 VII.B.5.7.1. PSUR sub-section “Completed clinical trials” ...............................................2152 VII.B.5.7.2. PSUR sub-section “Ongoing clinical trials”...................................................2153 VII.B.5.7.3. PSUR sub-section “Long term follow-up” ....................................................2154 VII.B.5.7.4. PSUR sub-section “Other therapeutic use of medicinal product”.....................2155 VII.B.5.7.5. PSUR sub-section “New safety data related to fixed combination therapies”....2156 VII.B.5.8. PSUR section “Findings from non-interventional studies” .................................2257 VII.B.5.9. PSUR section “Information for other clinical trials and sources” ........................2258 VII.B.5.9 1. PSUR sub-section “Other clinical trials”.......................................................2259 VII.B.5.9 2. PSUR sub-section “Medication errors” ........................................................2260 VII.B.5.10. PSUR section “Non-clinical data”.................................................................2261 VII.B.5.11. PSUR section “Literature” ..........................................................................2362 VII.B.5.12. PSUR section “Other periodic reports” .........................................................2363 VII.B.5.13. PSUR section “Lack of efficacy in controlled clinical trials” ..............................2464 VII.B.5.14. PSUR section “Late-breaking information” ...................................................2465 VII.B.5.15. PSUR section “Overview of signals: new, ongoing, or closed” .........................2466 VII.B.5.16. PSUR section “Signal and risk evaluation”....................................................2567 VII.B.5.16.1. PSUR sub-section “Summary of safety concerns”.......................................2668 VII.B.5.16.2. PSUR sub-section “Signal evaluation”.......................................................2769 VII.B.5.16.3. PSUR sub-section “Evaluation of risks and new information” .......................2870 VII.B.5.16.4. PSUR sub-section “Characterisation of risks” .............................................2971 VII.B.5.16.5. PSUR sub-section: “Effectiveness of risk minimisation (if applicable)”...........3072
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 4/69 VII.B.5.17. PSUR section “Benefit evaluation”...............................................................3073 VII.B.5.17.1. PSUR sub-section “Important baseline efficacy and effectiveness information”74 ..............................................................................................................................3075 VII.B.5.17.2. PSUR sub-section “Newly identified information on efficacy and effectiveness”76 ..............................................................................................................................3077 VII.B.5.17.3. PSUR sub-section “Characterisation of benefits” ........................................3178 VII.B.5.18. PSUR section “Integrated benefit-risk analysis for authorised indications”........3179 VII.B.5.18.1. PSUR sub-section “Benefit-risk context - medical need and important80 alternatives”.............................................................................................................3281 VII.B.5.18.2. PSUR sub-section “Benefit-risk analysis evaluation” ...................................3282 VII.B.5.19. PSUR section “Conclusions and actions” ......................................................3383 VII.B.5.20. Appendices to the PSUR ............................................................................3384 VII.B.5.21. Mapping signals and risks to PSUR sections/sub-sections...............................3485 VII.B.6. Quality systems for PSURs at the level of marketing authorisation holders ...........3586 VII.B.7. Training of staff members related to the PSUR process ......................................3687 VII.C. Operation of the EU network ........................................................... 3688 VII.C.1. PSUR process in the EU - General process........................................................3689 VII.C.2. Standard submission schedule of PSURs ..........................................................3890 VII.C.3. List of European Union reference dates and frequency of submission of PSURs .....3891 VII.C.3.1. Objectives of the EU reference dates list .......................................................3892 VII.C.3.2. Description of the EU reference dates list ......................................................3993 VII.C.3.3. Application of the list of EU reference dates to submission of PSURs .................4094 VII.C.3.3.1. Submission of PSURs for medicinal products: general requirement ................4095 VII.C.3.3.2. Submission of PSURs for generic, well-established use, traditional herbal and96 homeopathic medicinal products .................................................................................4197 VII.C.3.3.3. Submission of PSURs for fixed dose combination products ............................4398 VII.C.3.3.4. Submission of PSURs on demand of a competent authority in a Member State 4399 VII.C.3.4. Criteria used for defining the frequency of submission of PSURs.......................43100 VII.C.3.5. Maintenance of the list of EU reference dates.................................................44101 VII.C.3.5.1. General principles....................................................................................44102 VII.C.3.5.2. Requests from marketing authorisation holders to amend the list of EU103 reference dates ........................................................................................................46104 VII.C.3.6. Publication of the list ..................................................................................46105 VII.C.3.7. Amendment of the marketing authorisation according to the list of EU reference106 dates.......................................................................................................................46107 VII.C.4. Processes for PSUR Assessment in the EU network............................................46108 VII.C.4.1. PSURs for purely nationally authorised medicinal products ..............................47109 VII.C.4.2. Medicinal products authorised in more than one Member State ........................48110 VII.C.4.2.1. Assessment of PSURs for a single centrally authorised medicinal product .......48111 VII.C.4.2.2. Assessment of PSURs for medicinal products subject to different marketing112 authorisations containing the same active substance (EU single assessment) ...................51113 VII.C.4.2.3. Single assessment including at least one centrally authorised product leading to114 a CHMP opinion ........................................................................................................54115 VII.C.4.2.4. Single assessment not including centrally authorised product leading to a CMDh116 position ...................................................................................................................56117 VII.C.4.3. Relationship between PSUR and risk management plan...................................57118 VII.C.4.3.1. PSUR and risk management plan – common modules ..................................57119 VII.C.5. EU-specific requirements for periodic safety update reports................................58120
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 5/69 VII.C.5.1. PSUR EU regional appendix, sub-section “Proposed product information” ..........58121 VII.C.5.2. PSUR EU regional appendix, sub-section “Proposed additional pharmacovigilance122 and risk minimisation activities”..................................................................................59123 VII.C.5.3. PSUR EU regional appendix, sub-section “Summary of ongoing safety concerns” 59124 VII.C.5.4. PSUR EU regional appendix, sub-section “Reporting of results from post-125 authorisation safety studies” ......................................................................................59126 VII.C.5.5. PSUR EU regional appendix, sub-section “Effectiveness of risk minimisation” .....59127 VII.C.6. Quality systems and record management systems for PSURs in the EU network ...60128 VII.C.6.1. Quality systems and record management systems at the level of the marketing129 authorisation holder ..................................................................................................60130 VII.C.6.2. Quality systems and record management systems at the level of the European131 Medicines Agency......................................................................................................61132 VII.C.6.3. Quality systems and record management systems at the level of the competent133 authorities in Member States......................................................................................62134 VII.C.7. Transparency ...............................................................................................63135 VII.C.7.1. Publication of PSUR-related documents on the European medicines and national136 medicines web-portals...............................................................................................63137 VII.C.8. Renewal of marketing authorisations ...............................................................63138 VII.C.9. Transition and interim arrangements ...............................................................64139 VII.C.9.1. Submission and availability of documents before the Agency’s repository is in140 place.......................................................................................................................64141 VII.C.9.2. Quality systems and record management systems at the level of the competent142 authorities in Member States......................................................................................65143 VII.C.9.3. Publication of the EU list of union references dates and start of the EU-PSUR single144 assessment procedure...............................................................................................65145 VII.APPENDICES ....................................................................................... 66146 VII.Appendix 1. Examples of tabulations for estimated exposure and adverse147 events/reactions data................................................................................................66148 VII.Appendix 2. Example of tabular summary of safety signals that were ongoing or closed149 during the reporting interval.......................................................................................68150 151 152
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 6/69 VII.A. Introduction153 Periodic safety update reports (PSURs) are pharmacovigilance documents intended to provide an154 evaluation of the risk-benefit balance of a medicinal product for submission by marketing authorisation155 holders at defined time points during the post-authorisation phase.156 The legal requirements for submission of PSURs are established in Regulation (EC) No 726/2004,157 Directive 2001/83/EC and in the Commission Implementing Regulation (EU) No 520/2012 on the158 performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 and Directive159 2001/83/EC (hereinafter referred to as IR). All applicable legal requirements in this Module are160 referenced in the way explained in the GVP Introductory Cover Note and are usually identifiable by the161 modal verb “shall”. Guidance for the implementation of legal requirements is provided using the modal162 verb “should”.163 The format of PSURs shall follow the structure described in the IR Article 35. This Module provides164 guidance on the preparation, submission and assessment of PSURs.165 The scope, objectives, format and content of the PSUR are described in VII.B.. The required format166 and content of PSURs in the EU are based on those for the Periodic Benefit Risk Evaluation Report167 (PBRER) described in the ICH-E2C(R2) guideline (see Annex IV ICH-E2C(R2)). The PBRER format168 replaces the PSUR format previously described in the ICH-E2C(R1). In line with the EU legislation, the169 report is described as PSUR in the GVP Modules.170 Further details and guidance for the submission of PSURs in the EU, including the list of Union171 references dates and frequency of submission are provided in VII.C., which also covers the single EU172 assessment of PSURs in VII.C.4.. Details related to the quality system are provided in VII.C.6. and the173 publication of PSUR-related documents in VII.C.7. as transparency provisions.174 Each marketing authorisation holder shall be responsible for submitting PSURs for its own products175 [DIR Art 107b] [REG Art 28 (2)] and should submit PSURs to the Agency (see VII.C.9. for transitional176 arrangements) according to the following timelines:177  within 70 calendar days of the data lock point (day 0) for PSURs covering intervals up to 12178 months (including intervals of exactly 12 months); and179  within 90 calendar days of the data lock (day 0) point for PSURs covering intervals in excess of 12180 months;181  the timeline for the submission of ad hoc PSURs requested by competent authorities will normally182 be specified in the request, otherwise the ad hoc PSURs should be submitted within 90 calendar183 days of the data lock point.184 It should be noted that detailed listings of individual cases shall not be included systematically [IR Art185 34(4)]. The PSUR should focus on summary information, scientific safety assessment and integrated186 benefit-risk evaluation.187 Recital 23 of Directive 2010/84/EU explains that the obligations imposed in respect of PSURs should be188 proportionate to the risks posed by medicinal products. PSUR reporting should therefore be linked to189 the risk management systems of a medicinal product (see Module V). The “modular approach” of the190 PSUR described in VII.B.5. aims to minimise duplication and improve efficiency during the preparation191 and review of PSURs along with other regulatory documents such as the development safety update192 report (DSUR)1 or the safety specification in the Risk Management Plan (RMP), by enabling the193 1 See Detailed Guidance on the Collection, Verification and Presentation of Adverse Event/Reaction Reports Arising from Clinical Trials on Medicinal Products for Human Use; available on http://ec.europa.eu/health/documents/eudralex/vol-10/
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 7/69 common content of particular sections where appropriate to be utilised interchangeably across different194 PSURs, DSURs and RMPs.195 The 2010 amendment of the legislation also waives the obligation to submit PSURs routinely for196 generic medicinal products (authorised under DIR Art 10(1)), well-established use medicinal products197 (authorised under DIR Art 10a), homeopathic medicinal products (authorised under DIR Art 14) and198 traditional herbal medicinal products (authorised under DIR Art 16a), [DIR Art 107b(3)]. For such199 products, PSURs shall be submitted where there is a condition in the marketing authorisation or when200 requested by a competent authority in a Member State on the basis of concerns relating to201 pharmacovigilance data or due to the lack of PSURs for an active substance after its authorisation [DIR202 Art 107b(3)(a) and (3)(b)].203 Competent authorities in the Member States shall assess PSURs to determine whether there are new204 risks or whether risks have changed or whether there are changes to the risk-benefit balance of205 medicinal products [DIR Art 107d].206 In order to increase the shared use of resources between competent authorities in Member States, a207 single assessment of PSURs should be performed in the EU for different medicinal products containing208 the same active substance or the same combination of active substances authorised in more than one209 Member State for which a Union reference date and frequency of submission of PSURs has been210 established. The EU single assessment can include joint assessment for medicinal products authorised211 through either national or centralised procedures for marketing authorisation. The Agency shall make212 available a list of Union reference dates and frequency of submission [REG Art 26(g)] which will be213 legally binding.214 As part of the assessment, it should be considered whether further investigations need to be carried215 out and whether any action concerning the marketing authorisations of products containing the same216 active substance or the same combination of active substances, and their product information is217 necessary.218 The Agency shall make the PSURs available to the competent authorities in Member States, members219 of the Pharmacovigilance Risk Assessment Committee (PRAC), of the Committee for Medicinal Products220 for Human use (CHMP) and of the Coordination Group for Mutual Recognition and Decentralised221 Procedures - Human (CMDh) and the European Commission by means of a PSUR repository [DIR Art222 107b(2)].223 VII.B. Structures and processes224 VII.B.1. Objectives of the periodic update safety report (PSUR)225 The main objective of a PSUR is to present a comprehensive, concise and critical analysis of the risk-226 benefit balance of the medicinal product taking into account new or emerging information in the227 context of cumulative information on risks and benefits. The PSUR is therefore a tool for post-228 authorisation evaluation at defined time points in the lifecycle of a product.229 For the purposes of lifecycle benefit-risk management, it is necessary to continue evaluating the risks230 and benefits of a medicine in everyday medical practice and long term use in the post-authorisation231 phase. This may extend to evaluation of populations and endpoints that could not be investigated in232 the pre-authorisation clinical trials. A different risk-benefit balance may emerge as pharmacovigilance233 reveals further information about safety. The marketing authorisation holder should therefore re-234 evaluate the risk-benefit balance of its own medicinal products in populations exposed. This structured235 evaluation should be undertaken in the context of ongoing pharmacovigilance (see Module XII) and236
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 8/69 risk management (see Module V) to facilitate optimisation of the risk-benefit balance through effective237 risk minimisation.238 A PSUR should not be used to provide initial notification of significant new safety information or, as a239 general rule, provide the means by which new safety issues are detected, or new efficacy data are240 submitted (see Module IX and XII).241 VII.B.2. Principles for the evaluation of the risk-benefit balance within242 PSURs and scope of the information to be included243 Benefit-risk evaluation should be carried out throughout the lifecycle of the medicinal product to244 promote and protect public health and to enhance patient safety through effective risk minimisation.245 After a marketing authorisation is granted, it is necessary to continue evaluating the benefits and risks246 of medicinal products in actual use and/or long term use, to confirm that the risk-benefit balance247 remains favourable.248 The analysis of the risk-benefit balance should incorporate an evaluation of the safety, efficacy and249 effectiveness information that becomes available2 , with reasonable and appropriate effort, during the250 reporting interval for the medicinal product in the context of what was known previously.251 The risk evaluation should be based on all uses of the medicinal product. The scope includes evaluation252 of safety in real medical practice including use in unauthorised indications and use which is not in line253 with the product information. If use of the medicinal product is identified where there are critical gaps254 in knowledge for specific safety issues or populations, such use should be reported in the PSUR (e.g.255 use in paediatric population or in pregnant women). Sources of information on use outside256 authorisation may include drug utilisation data, information from spontaneous reports and publications257 in the literature.258 The scope of the benefit information should include both clinical trial and real world data in authorised259 indications.260 The integrated benefit-risk evaluation should be based on all authorised indications but should261 incorporate the evaluation of risks in all use of the medicinal product (including use in unauthorised262 indications).263 The evaluation should involve:264 1. Critically examining the information which has emerged during the reporting interval to determine265 whether it has generated new signals, led to the identification of new potential or identified risks or266 contributed to knowledge of previously identified risks.267 2. Critically summarising relevant new safety, efficacy and effectiveness information that could have268 an impact on the risk-benefit balance of the medicinal product.269 3. Conducting an integrated benefit-risk analysis for all authorised indications based on the270 cumulative information available since the development international birth date (DIBD), the date of271 first authorisation for the conduct of an interventional clinical trial in any country. For the cases272 where the DIBD is unknown or the marketing authorisation holder does not have access to data273 from the clinical development period, the earliest possible applicable date should be used as274 starting point for the inclusion and evaluation of the cumulative information.275 2 The ICH-E2C(R2) guideline should not serve to limit the scope of the information to be provided in the benefit-risk evaluation of a medicinal product. Please refer to the applicable laws and regulations in the countries and regions. For EU specific requirements, see VII.C.5..
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 9/69 4. Summarising any risk minimisation actions that may have been taken or implemented during the276 reporting interval, as well as risk minimisation actions that are planned to be implemented.277 5. Outlining plans for signal or risk evaluations including timelines and/or proposals for additional278 pharmacovigilance activities.279 VII.B.3. Principles for the preparation of PSURs280 Unless otherwise specified by competent authorities, the marketing authorisation holder shall prepare281 a single PSUR for all its medicinal products containing the same active substance with information282 covering all the authorised indications, route of administration, dosage forms and dosing regiments,283 irrespective of whether authorised under different names and through separate procedures. Where284 relevant, data relating to a particular indication, dosage form, route of administration or dosing285 regimen, shall be presented in a separate section of the PSUR and any safety concerns shall be286 addressed accordingly [IR Art 34(6)]. There might be exceptional scenarios where the preparation of287 separate PSURs might be appropriate, for instance, in the event of different formulations for entirely288 different indications. In this case, agreement should be obtained from the relevant competent289 authorities preferably at the time of authorisation.290 Case narratives shall be provided in the relevant risk evaluation section of the PSUR where integral to291 the scientific analysis of a signal or safety concern [IR Art 34(4)]. In this context, the term “case292 narratives” refers to clinical evaluations of individual cases rather than the CIOMS narratives. It should293 not be necessary to provide the actual CIOMS narrative text included in the individual case safety294 report (ICSR) but rather a clinical evaluation of important or illustrative cases in the context of the295 evaluation of the safety concern/signal.296 When data received at the marketing authorisation holder from a partner might contribute297 meaningfully to the safety, benefit and/or benefit-risk analyses and influence the reporting marketing298 authorisation holder’s product information, these data should be included and discussed in the PSUR.299 The format and table of contents of all PSURs shall be as described in the IR Art 35 and each report300 should include interval as well as cumulative data. As the PSUR should be a single stand–alone301 document for the reporting interval, based on cumulative data, summary bridging reports and302 addendum reports, introduced in ICH-E2C(R1) guideline, will not be accepted.303 VII.B.4. Reference information304 Risk minimisation activities evaluated in the PSUR include updates to the product information.305 The reference product information for the PSUR should include “core safety” and “authorised306 indications” components. In order to facilitate the assessment of benefit and risk-benefit balance by307 indication in the evaluation sections of the PSUR, the reference product information document should308 list all authorised indications in ICH countries3 or regions. When the PSUR is also submitted to other309 countries in which there are additional locally authorised indications, these indications may be either310 added to the reference product information or handled as a regional appendix as considered most311 appropriate by the marketing authorization holder. The basis for the benefit evaluation should be the312 baseline important efficacy and effectiveness information summarised in the PSUR section 17.1313 (“Important baseline efficacy and effectiveness information”).314 Information related to a specific indication, formulation or route of administration should be clearly315 identified in the reference product information.316 3 http://www.ich.org/
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 10/69 The following possible options can be considered by the marketing authorisation holders when317 selecting the most appropriate reference product information for a PSUR:318  Company core data sheet (CCDS)319  It is common practice for marketing authorisation holders to prepare their own company core320 data sheet which covers data relating to safety, indications, dosing, pharmacology, and other321 information concerning the product. The core safety information contained within the CCDS is322 referred to as the company core safety information (CCSI). A practical option for the purpose323 of the PSUR is for each marketing authorisation holder to use the CCDS in effect at the end of324 the reporting interval, as reference product information for both the risk sections of the PSUR325 as well as the main authorised indications for which benefit is evaluated.326  When the CCDS does not contain information on authorised indications, the marketing327 authorisation holder should clearly specify which document is used as reference information for328 the authorised indications in the PSUR.329  Other options for the reference product information330  When no CCDS or CCSI exist for a product (e.g. where the product is authorised in only one331 country or region, or for established/generics products on the market for many years), the332 marketing authorisation holder should clearly specify the reference information being used.333 This may comprise national or regional product information such as the EU summary of product334 characteristics (SmPC).335  Where the reference information for the authorised indications is a separate document to the336 reference safety information (the core safety information contained within the reference337 product information), the version in effect at the end of the reporting interval should be338 included as an appendix to the PSUR (see VII.B.5.20.).339 The marketing authorisation holder should continuously evaluate whether any revision of the reference340 product information/reference safety information is needed whenever new safety information is341 obtained during the reporting interval and ensure that significant changes made over the interval are342 described in PSUR section 4 (“Changes to the reference safety information”) and where relevant,343 discussed in PSUR section 16 (“Signal and risk evaluation”). These changes may include:344  changes to contraindications, warnings/precautions sections;345  addition to adverse reactions and interactions;346  addition of important new information on use in overdose; and347  removal of an indication or other restrictions for safety or lack of efficacy reasons.348 The marketing authorisation holder should provide a clean copy of all versions of the reference product349 information in effect at the end of the reporting interval (e.g. different formulations included in the350 same PSUR) as an appendix to the PSUR (see VII.B.5.20.). The reference product information should351 be dated and version controlled.352 Where new information on safety that could warrant changes to the authorised product information353 (e.g. new adverse drug reaction, warning or contraindication) has been added to the reference safety354 information during the period from the data lock point to the submission of the PSUR, this information355 should be included in the PSUR section 14 (“Late-breaking information”), if feasible.356 If stipulated by applicable regional requirements, the marketing authorisation holder should provide, in357 the regional appendix, information on any final, ongoing and proposed changes to the national or local358 authorised product information (see VII.C.5.)359
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 11/69 The marketing authorisation holder should clearly highlight differences that may have an impact on360 labelling changes (e.g. adverse drug reactions, contraindications, warnings, interactions, overdose)361 between the version of the reference safety information in effect at the end of the reporting interval,362 taking into account any changes made during the late-breaking period, and their proposals for the local363 authorised product information based on the evaluation of the information contained in the PSUR.364 These differences should be included in PSUR regional appendix (see VII.B.5.20. and VII.C.5.2).365 VII.B.5. Format and contents of the PSUR366 The PSUR shall be based on all available data and shall focus on new information which has emerged367 since the data lock point of the last PSUR [IR Art 34(1)]. Cumulative information should be taken into368 account when performing the overall safety evaluation and integrated benefit-risk assessment.369 Because clinical development of a medicinal product frequently continues following marketing370 authorisation, relevant information from post-authorisation studies or clinical trials in unauthorised371 indications or populations should also be included in the PSUR. Similarly, as knowledge of the safety of372 a medicinal product may be derived from evaluation of other data associated with off-label use, such373 knowledge should be reflected in the risk evaluation where relevant and appropriate.374 The PSUR shall provide summaries of data relevant to the benefits and risks of the medicinal product,375 including results of all studies with a consideration of their potential impact on the marketing376 authorisation [DIR Art 107b(1)(a)].377 Examples of sources of efficacy, effectiveness and safety information that may be used in the378 preparation of PSURs include the following:379  non-clinical studies;380  spontaneous reports (e.g. on the marketing authorisation holder’s safety database);381  active surveillance systems (e.g. sentinel sites);382  investigations of product quality;383  product usage data and drug utilisation information;384  clinical trials, including research in unauthorised indications or populations;385  observational studies, including registries;386  patient support programs;387  systematic reviews and meta-analysis;388  marketing authorisation holders sponsored websites4 ;389  published scientific literature or reports from abstracts, including information presented at scientific390 meetings;391  unpublished manuscripts;392  licensing partners, other sponsors or academic institutions and research networks;393  competent authorities (worldwide).394 The above list is not intended to be all inclusive, and additional data sources may be used by the395 marketing authorisation holder to present safety, efficacy and effectiveness in the PSUR and to396 4 ICH-E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting.
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 12/69 evaluate the risk-benefit balance, as appropriate to the product and its known and emerging important397 benefits and risks. When desired by the marketing authorisation holder, a list of the sources of398 information used to prepare the PSUR can be provided as an appendix to the PSUR.399 A PSUR shall be prepared following the full modular structure set out in Annex II of the IR [IR Art 35].400 For the purposes of this Module, sources of information include data regarding the active substance(s)401 included in the medicinal product, or the medicinal product that the marketing authorisation holder402 may reasonably be expected to have access to and that are relevant to the evaluation of the safety,403 and/or risk-benefit balance. It is therefore recognised that while the same format (as defined in the IR)404 shall be followed for all products, the extent of the information provided may vary where justified405 according to what is accessible to the marketing authorisation holder. For example, for a marketing406 authorisation holder sponsored clinical trial, there should be access to patient level data while for a407 clinical trial not sponsored by the marketing authorisation holder, only the published report may be408 accessible.409 The level of detail provided in certain sections of the PSUR should depend on known or emerging410 important information on the medicinal product’s benefits and risks. This approach is applicable to411 those sections of the PSUR in which there is evaluation of information about safety, efficacy,412 effectiveness, safety signals and risk-benefit balance.413 When preparing the PSUR, the ICH-E2C(R2) guideline (see Annex IV ICH-E2C(R2)) on PBRER should414 also be applied. Guidance on the titles, order and content of the PSUR sections is provided in VII.B.5.1.415 to VII.B.5.21.. When no relevant information is available for any of the sections, this should be stated.416  Part I: Title page including signature5 417  Part II: Executive Summary418  Part III: Table of Contents419 1. Introduction420 2. Worldwide marketing authorisation status421 3. Actions taken in the reporting interval for safety reasons422 4. Changes to reference safety information423 5. Estimated exposure and use patterns424 5.1. Cumulative subject exposure in clinical trials425 5.2. Cumulative and interval patient exposure from marketing experience426 6. Data in summary tabulations427 6.1. Reference information428 6.2. Cumulative summary tabulations of serious adverse events from clinical trials429 6.3. Cumulative and interval summary tabulations from post-marketing data sources430 7. Summaries of significant findings from clinical trials during the reporting interval431 7.1. Completed clinical trials432 5 For PSURs submission in the EU, it is at the discretion of the QPPV to determine the most appropriate person to sign the document according to the marketing authorisation holder structure and responsibilities. A statement confirming the designation by the QPPV should be included. No delegation letters should be submitted.
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 13/69 7.2. Ongoing clinical trials433 7.3. Long-term follow-up434 7.4. Other therapeutic use of medicinal product435 7.5. New safety data related to fixed combination therapies436 8. Findings from non-interventional studies437 9. Information from other clinical trials and sources438 9.1. Other clinical trials439 9.2. Medication errors440 10. Non-clinical Data441 11. Literature442 12. Other periodic reports443 13. Lack of efficacy in controlled clinical trials444 14. Late-breaking information445 15. Overview of signals: new, ongoing or closed446 16. Signal and risk evaluation447 16.1. Summaries of safety concerns448 16.2. Signal evaluation449 16.3. Evaluation of risks and new information450 16.4. Characterisation of risks451 16.5. Effectiveness of risk minimisation (if applicable)452 17. Benefit evaluation453 17.1. Important baseline efficacy and effectiveness information454 17.2. Newly identified information on efficacy and effectiveness455 17.3. Characterisation of benefits456 18. Integrated benefit-risk analysis for authorised indications457 18.1. Benefit-risk context – Medical need and important alternatives458 18.2. Benefit-risk analysis evaluation459 19. Conclusions and actions460 20. Appendices to the PSUR461 PSUR title page462 The title page should include the name of the medicinal product(s)6 and substance, international birth463 date (IBD) (the date of the first marketing authorisation for any product containing the active464 6 For PSURs covering multiple products, for practical reasons, this information may be provided in the PSUR Cover Page (See Annex II)
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 14/69 substance granted to any company in any country in the world), reporting interval, date of the report,465 marketing authorisation holder details and statement of confidentiality of the information included in466 the PSUR.467 The title page shall also contain the signature.468 PSUR executive summary469 An executive summary should be placed immediately after the title page and before the table of470 contents. The purpose of the executive summary is to provide a concise summary of the content and471 the most important information in the PSUR and should contain the following information:472  introduction and reporting interval;473  medicinal product(s), therapeutic class(es), mechanism(s) of action, indication(s), pharmaceutical474 formulation(s), dose(s) and route(s) of administration;475  estimated cumulative clinical trials exposure;476  estimated interval and cumulative exposure from marketing experience;477  number of countries in which the medicinal product is authorised;478  summary of the overall benefit-risk analysis evaluation (based on sub-section 18.2 “benefit-risk479 analysis evaluation” of the PSUR);480  actions taken and proposed for safety reasons, (e.g. significant changes to the reference product481 information, or other risk minimisation activities);482  conclusions.483 PSUR table of contents484 The executive summary should be followed by the table of contents.485 VII.B.5.1. PSUR section “Introduction”486 The marketing authorisation holder should briefly introduce the product(s) so that the PSUR “stands487 alone” but it is also placed in perspective relative to previous PSURs and circumstances. The488 introduction should contain the following information:489  IBD, and reporting interval;490  medicinal product(s), therapeutic class(es), mechanism(s) of action, authorised indication(s),491 pharmaceutical form(s), dose(s) and route(s) of administration;492  a brief description of the population(s) being treated and studied;493 VII.B.5.2. PSUR section “Worldwide marketing authorisation status"494 This section of the PSUR should contain a brief narrative overview including: date of the first495 authorisation worldwide, indications(s), authorised dose(s), and where authorised.496
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 15/69 VII.B.5.3. PSUR section “Actions taken in the reporting interval for safety497 reasons”498 This section of the PSUR should include a description of significant actions related to safety that have499 been taken worldwide during the reporting interval, related to either investigational uses or marketing500 experience by the marketing authorisation holder, sponsors of clinical trial(s), data monitoring501 committees, ethics committees or competent authorities that had either:502  a significant influence on the risk-benefit balance of the authorised medicinal product; and/or503  an impact on the conduct of a specific clinical trial(s) or on the overall clinical development504 programme.505 If known, the reason for each action should be provided and any additional relevant information should506 be included as appropriate. Relevant updates to previous actions should also be summarised in this507 section.508 Examples of significant actions taken for safety reasons include:509 Actions related to investigational uses:510  refusal to authorise a clinical trial for ethical or safety reasons;511  partial7 or complete clinical trial suspension or early termination of an ongoing clinical trial because512 of safety findings or lack of efficacy;513  recall of investigational drug or comparator;514  failure to obtain marketing authorisation for a tested indication including voluntary withdrawal of a515 marketing authorisation application;516  risk management activities, including:517  protocol modifications due to safety or efficacy concerns (e.g. dosage changes, changes in518 study inclusion/exclusion criteria, intensification of subject monitoring, limitation in trial519 duration);520  restrictions in study population or indications;521  changes to the informed consent document relating to safety concerns;522  formulation changes;523  addition by regulators of a special safety-related reporting requirement;524  issuance of a communication to investigators or healthcare professionals; and525  plans for new studies to address safety concerns.526 Actions related to marketing experience:527  failure to obtain or apply for a marketing authorisation renewal;528  withdrawal or suspension of a marketing authorisation;529  actions taken due to product defects and quality issues;530  suspension of supply by the marketing authorisation holder;531 7 “Partial suspension” might include several actions (e.g. suspension of repeat dose studies, but continuation of single dose studies; suspension of trials in one indication, but continuation in another, and/or suspension of a particular dosing regimen in a trial but continuation of other doses). ICH-E2C(R2) guideline (see Annex IV).
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 16/69  risk management activities including:532  significant restrictions on distribution or introduction of other risk minimisation measures;533  significant safety-related changes in labelling documents including restrictions on use or534 population treated;535  communications to health care professionals; and536  new post-marketing study requirement(s) imposed by competent authorities.537 VII.B.5.4. PSUR section “Changes to reference safety information”538 This PSUR section should list any significant changes made to the reference safety information within539 the reporting interval. Such changes might include information relating to contraindications, warnings,540 precautions, serious adverse drug reactions, interactions, important findings from ongoing or541 completed clinical trials and significant non-clinical findings (e.g. carcinogenicity studies). Specific542 information relevant to these changes should be provided in the appropriate sections of the PSUR.543 VII.B.5.5. PSUR section “Estimated exposure and use patterns”544 PSURs shall provide an accurate estimate of the population exposed to the medicinal product, including545 all data relating to the volume of sales and volume of prescriptions. This estimate of exposure shall be546 accompanied by a qualitative and quantitative analysis of actual use, which shall indicate, where547 appropriate, how actual use differs from the indicated use based on all data available to the marketing548 authorisation holder, including the results of observational or drug utilisation studies [IR Art 34 (2)].549 This PSUR section should provide estimates of the size and nature of the population exposed to the550 medicinal product including a brief description of the method(s) used to estimate the subject/patient551 exposure and the limitations of that method.552 Consistent methods for calculating subject/patient exposure should be used across PSURs for the same553 medicinal product. If a change in the method is appropriate, both methods and calculations should be554 provided in the PSUR introducing the change and any important difference between the results using555 the two methods should be highlighted.556 VII.B.5.5.1. PSUR sub-section “Cumulative subject exposure in clinical trials”557 This section of the PSUR should contain the following information on the patients studied in clinical558 trials sponsored by the marketing authorisation holder, if applicable presented in tabular formats:559  cumulative numbers of subjects from ongoing and completed clinical trials exposed to the560 investigational medicinal product, placebo, and/or active comparator(s) since the DIBD. It is561 recognised that for “old products”, detailed data might not available;562  more detailed cumulative subject exposure in clinical trials should be presented if available (e.g.563 sub-grouped by age, sex, and racial/ethnic group for the entire development programme);;564  important differences among trials in dose, routes of administration, or patient populations can be565 noted in the tables, if applicable, or separate tables can be considered;566  if clinical trials have been or are being performed in special populations (e.g. pregnant women;567 patients with renal, hepatic, or cardiac impairment; or patients with relevant genetic568 polymorphisms), exposure data should be provided as appropriate;569
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 17/69  when there are substantial differences in time of exposure between subjects randomised to the570 investigational medicinal product or comparator(s), or disparities in length of exposure between571 clinical trials, it can be useful to express exposure in subject-time (subject-days, -months, or -572 years);573  investigational drug exposure in healthy volunteers might be less relevant to the overall safety574 profile, depending on the type of adverse reaction, particularly when subjects are exposed to a575 single dose. Such data can be presented separately with an explanation as appropriate;576  if the serious adverse events from clinical trials are presented by indication in the summary577 tabulations, the patient exposure should also be presented by indication, where available;578  for individual trials of particular importance, demographic characteristics should be provided579 separately.580 Examples of tabular format for the estimated exposure in clinical trials are presented in VII. Appendix581 1, Tables VII.2, VII.3 and VII.4.582 VII.B.5.5.2. PSUR sub-section “Cumulative and interval patient exposure from marketing583 experience”584 Separate estimates should be provided for cumulative exposure (since the IBD), when possible, and585 interval exposure (since the data lock point of the previous PSUR). Although it is recognised that it is586 often difficult to obtain and validate exposure data, the number of patients exposed should be provided587 whenever possible, along with the method(s) used to determine the estimate. Justification should be588 provided if it is not possible to estimate the number of patients exposed. In this case, alternative589 estimates of exposure, if available, should be presented along with the method(s) used to derive them.590 Examples of alternative measures of exposure include patient-days of exposure and number of591 prescriptions. Only if such measures are not available, measures of drug sales, such as tonnage or592 dosage units, may be used. The concept of a defined daily dose may also be used to arrive at patient593 exposure estimates.594 The data should be presented according to the following categories:595 1. Post-authorisation (non-clinical trial) exposure:596 An overall estimation of patient exposure should be provided. In addition, the data should be597 routinely presented by sex, age, indication, dose, formulation and region, where applicable.598 Depending upon the product, other variables may be relevant, such as number of vaccination599 courses, route(s) of administration, and duration of treatment.600 When there are patterns of reports indicating a safety signal, exposure data within relevant601 subgroups should be presented, if possible.602 2. Post-authorisation use in special populations:603 Where post-authorisation use has occurred in special populations, available information regarding604 cumulative patient numbers exposed and the method of calculation should be provided. Sources of605 such data would include non-interventional studies designed to obtain this information, including606 registries. Populations to be considered for discussion include, but might not be limited to:607  paediatric population;608  elderly population;609  pregnant or lactating women;610
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 18/69  patients with hepatic and/or renal impairment;611  patients with other relevant co-morbidity;612  patients with disease severity different from that studied in clinical trials;613  sub-populations carrying relevant genetic polymorphism(s);614  populations with specific racial and/or ethnic origins.615 3. Other post-authorisation use:616 If the marketing authorisation holder becomes aware of a pattern of use of the medicinal product,617 which may be regional, considered relevant for the interpretation of safety data, provide a brief618 description thereof. Examples of such patterns of use may include overdose, abuse, misuse and619 use beyond the recommendation(s) in the reference product information (e.g. an anti-epileptic620 drug used for neuropathic pain and/or prophylaxis of migraine headaches). If known, the621 marketing authorisation holder may briefly comment on whether other use beyond the622 recommendation(s) in the reference product information is supported by clinical guidelines, clinical623 trial evidence, or an absence of authorised alternative treatments. If quantitative use information624 is available, it should be provided. For purposes of identifying patterns of use outside the terms of625 the reference product information, the marketing authorisation holder should use the appropriate626 sections of the reference product information that was in effect at the end of the reporting interval627 of the PSUR (e.g. authorised indication, contraindications).628 Examples of tabular format for the estimated exposure from marketing experience are presented in629 VII. Appendix 1, Tables VII.5 and VII.6.630 VII.B.5.6. PSUR section “Data in summary tabulations”631 The objective of this PSUR section is to present safety data through summary tabulations of serious632 adverse events from clinical trials, spontaneous serious and non-serious reactions from marketing633 experience (including reports from healthcare professionals, consumers, scientific literature, competent634 authorities (worldwide)) and serious reactions from non-interventional studies and other non-635 interventional solicited source. At the discretion of the marketing authorisation holder graphical636 displays can be used to illustrate specific aspects of the data when useful to enhance understanding.637 When the Medical Dictionary for Regulatory Activities (MedDRA) terminology is used for coding the638 adverse event/reaction terms, the preferred term (PT) level and system organ class (SOC) should be639 presented in the summary tabulations.640 The seriousness of the adverse events/reactions in the summary tabulations should correspond to the641 seriousness assigned to events/reactions included in the ICSRs using the criteria established in ICH-642 E2A8 (see Annex IV). When serious and non-serious events/reactions are included in the same ICSR,643 the individual seriousness per reaction should be reflected in the summary tabulations. Seriousness644 should not be changed specifically for the preparation of the PSURs.645 VII.B.5.6.1. PSUR sub-section “Reference information”646 This sub-section of the PSUR should specify the version(s) of the coding dictionary used for647 presentation of adverse events/reactions.648 8 ICH Topic E2A. Clinical safety data management: Definitions and standards for expedited reporting.
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 19/69 VII.B.5.6.2. PSUR sub-section “Cumulative summary tabulations of serious adverse events649 from clinical trials”650 This PSUR sub-section should provide background for the appendix that provides a cumulative651 summary tabulation of serious adverse events reported in the marketing authorisation holder’s clinical652 trials, from the DIBD to the data lock point of the current PSUR. The marketing authorisation holder653 should explain any omission of data (e.g. clinical trial data might not be available for products654 marketed for many years). The tabulation(s) should be organised by MedDRA SOC (listed in the655 internationally agreed order), for the investigational drug, as well as for the comparator arm(s) (active656 comparators, placebo) used in the clinical development programme. Data can be integrated across the657 programme. Alternatively, when useful and feasible, data can be presented by trial, indication, route of658 administration or other variables.659 This sub-section should not serve to provide analyses or conclusions based on the serious adverse660 events.661 The following points should be considered:662  Causality assessment is generally useful for the evaluation of individual rare adverse drug663 reactions. Individual case causality assessment has less value in the analysis of aggregate data,664 where group comparisons of rates are possible. Therefore, the summary tabulations should include665 all serious adverse events and not just serious adverse reactions for the investigational drug,666 comparators and placebo. It may be useful to give rates by dose.667  In general, the tabulation(s) of serious adverse events from clinical trials should include only those668 terms that were used in defining the case as serious and non-serious events should be included in669 the study reports.670  The tabulations should include blinded and unblinded clinical trial data. Unblinded serious adverse671 events might originate from completed trials and individual cases that have been unblinded for672 safety-related reasons (e.g. expedited reporting), if applicable. Sponsors of clinical trials and673 marketing authorisation holders should not unblind data for the specific purpose of preparing the674 PSUR.675  Certain adverse events can be excluded from the clinical trials summary tabulations, but such676 exclusions should be explained in the report. For example, adverse events that have been defined677 in the protocol as “exempt” from special collection and entry into the safety database because they678 are anticipated in the patient population, and those that represent study endpoints, can be679 excluded (e.g. deaths reported in a trial of a drug for congestive heart failure where all-cause680 mortality is the primary efficacy endpoint, disease progression in cancer trials).681 An example of summary tabulation of serious adverse events from clinical trials can be found in VII.682 Appendix 1 Table VII.7.683 VII.B.5.6.3. PSUR sub-section “Cumulative and interval summary tabulations from post-684 marketing data sources”685 This sub-section of the PSUR should provide background for the appendix that provides cumulative and686 interval summary tabulations of adverse reactions, from the IBD to the data lock point of the current687 PSUR. These adverse reactions are derived from spontaneous ICSRs including reports from healthcare688 professionals, consumers, scientific literature, competent authorities (worldwide) and from solicited689 non-interventional ICSRs including those from non-interventional studies9 . Serious and non-serious690 reactions from spontaneous sources, as well as serious adverse reactions from non-interventional691 9 ICH-E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting.
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 20/69 studies and other non-interventional solicited sources should be presented in a single table, with692 interval and cumulative data presented side-by-side. The table should be organised by MedDRA SOC693 (listed in the internationally agreed order). For special issues or concerns, additional tabulations of694 adverse reactions can be presented by indication, route of administration, or other variables.695 As described in ICH-E2D10 (see Annex IV) guideline, for marketed medicinal products, spontaneously696 reported adverse events usually imply at least a suspicion of causality by the reporter and should be697 considered to be suspected adverse reactions for regulatory reporting purposes.698 Analysis or conclusions based on the summary tabulations should not be provided in this PSUR sub-699 section.700 An example of summary tabulations of adverse drug reactions from post-marketing data sources can701 be found in VII. Appendix 1 Table VII.8.702 VII.B.5.7. PSUR section “Summaries of significant findings from clinical703 trials during the reporting interval”704 This PSUR section should provide a summary of the clinically important emerging efficacy and safety705 findings obtained from the marketing authorisation holder’s sponsored clinical trials during the706 reporting interval, from the sources specified in the sub-sections listed below. When possible and707 relevant, data categorised by sex and age (particularly paediatrics versus adults), indication, dose, and708 region should be presented.709 Signals arising from clinical trial sources should be tabulated in PSUR section 15 (“Overview on signals:710 new, ongoing or closed”). Evaluation of the signals, whether or not categorised as refuted signals or711 either potential or identified risk, that were closed during the reporting interval should be presented in712 PSUR section 16.2 (“Signal evaluation”). New information in relation to any previously known potential713 or identified risks and not considered to constitute a newly identified signal should be evaluated and714 characterised in PSUR sections 16.3 (“Evaluation of risks and new information”) and 16.4715 (“Characterisation of risks”) respectively.716 Findings from clinical trials not sponsored by the marketing authorisation holder should be described in717 the relevant sections of the PSUR.718 When relevant to the benefit-risk evaluation, information on lack of efficacy from clinical trials for719 treatments of non-life-threatening diseases in authorised indications should also be summarised in this720 section. Information on lack of efficacy from clinical trials with products intended to treat or prevent721 serious or life-threatening illness should be summarised in section 13 (“Lack of efficacy in controlled722 clinical trials”).723 In addition, the marketing authorisation holder should include an appendix listing the sponsored post-724 authorisation interventional trials with the primary aim of identifying, characterising, or quantifying a725 safety hazard or confirming the safety profile of the medicinal product that were completed or ongoing726 during the reporting interval. The listing should include the following information for each trial:727  study ID (e.g. protocol number or other identifier);728  study title (abbreviated study title, if applicable);729  study type (e.g. randomised clinical trial, cohort study, case-control study);730  population studied, including country and other relevant population descriptors (e.g. paediatric731 population or trial subjects with impaired renal function);732 10 See footnote 8.
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 21/69  study start (as defined by the marketing authorisation holder) and projected completion dates;733  status: ongoing (clinical trial has begun) or completed (clinical study report is finalised).734 VII.B.5.7.1. PSUR sub-section “Completed clinical trials”735 This sub-section of the PSUR should provide a brief summary of clinically important emerging efficacy736 and safety findings obtained from clinical trials completed during the reporting interval. This737 information can be presented in narrative format or as a synopsis11 . It could include information that738 supports or refutes previously identified safety concerns as well as evidence of new safety signals.739 VII.B.5.7.2. PSUR sub-section “Ongoing clinical trials”740 If the marketing authorisation holder is aware of clinically important information that has arisen from741 ongoing clinical trials (e.g. learned through interim safety analyses or as a result of unblinding of742 subjects with adverse events), this sub-section should briefly summarise the concern(s). It could743 include information that supports or refutes previously identified safety concerns, as well as evidence744 of new safety signals.745 VII.B.5.7.3. PSUR sub-section “Long term follow-up”746 Where applicable, this sub-section should provide information from long-term follow-up of subjects747 from clinical trials of investigational drugs, particularly advanced therapy products (e.g. gene therapy,748 cell therapy products and tissue engineered products).749 VII.B.5.7.4. PSUR sub-section “Other therapeutic use of medicinal product”750 This sub-section of the PSUR should include clinically important safety information from other751 programmes conducted by the marketing authorisation holder that follow a specific protocol, with752 solicited reporting as per ICH-E2D12 (e.g. expanded access programmes, compassionate use753 programmes, particular patient use, and other organised data collection).754 VII.B.5.7.5. PSUR sub-section “New safety data related to fixed combination therapies”755 Unless otherwise specified by national or regional regulatory requirements, the following options can756 be used to present data from combination therapies:757  If the active substance that is the subject of the PSURs is also authorised or under development as758 a component of a fixed combination product or a multi-drug regimen, this sub-section should759 summarise important safety findings from use of the combination therapy.760  If the product itself is a fixed combination product, this PSUR sub-section should summarise761 important safety information arising from the individual components whether authorised or under762 development.763 The information specific to the combination can be incorporated into a separate section(s) of the PSUR764 for one or all of the individual components of the combination.765 11 Examples of synopses can be found in ICH-E3: Structure and Content of Clinical Study Reports and CIOMS VII (Council for International Organizations of Medical Sciences (CIOMS). Development Safety Update Report (DSUR): Harmonizing the Format and Content for Periodic Safety Reporting During Clinical Trials - Report of CIOMS Working Group VII). Geneva: CIOMS; 2006. http://www.cioms.ch/. 12 ICH-E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting.
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 22/69 VII.B.5.8. PSUR section “Findings from non-interventional studies”766 This section should also summarise relevant safety information or information with potential impact in767 the benefit-risk assessment from marketing authorisation holder-sponsored non-interventional studies768 that became available during the reporting interval (e.g. observational studies, epidemiological studies,769 registries, and active surveillance programmes). This should include relevant information from drug770 utilisation studies when relevant to multiple regions (see VII.B.5.7. for the information that should be771 included in the listing)772 The marketing authorisation holder should include an appendix listing marketing authorisation holder-773 sponsored non-interventional studies conducted with the primary aim of identifying, characterising or774 quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the775 effectiveness of risk management measures which were completed or ongoing during the reporting776 interval.777 Final study reports completed during the reporting interval for the studies mentioned in the paragraph778 above should also be included in the regional appendix of the PSUR (see VII.B.5.20. and VII.C.5.4.).779 VII.B.5.9. PSUR section “Information for other clinical trials and sources”780 Other sources of information may include data collection outside of a study environment. Information781 obtained from reports of events or patterns of use which do not result in suspected adverse reactions782 may be included in sub-sections VII.B.5.9.1. and VII.B.5.9.2. For example, this would include available783 information on reports of asymptomatic overdose, abuse, use beyond that recommended in the784 reference product information, or use in special populations (see Module VI). Such information may be785 received via spontaneous reports, medical information queries, customer’s complaints, screening of786 digital media or via other information sources available to the marketing authorisation holder.787 Signals or risks identified from any information source and/or category of reports should be presented788 and evaluated in the relevant sections of the PSUR.789 VII.B.5.9 1. PSUR sub-section “Other clinical trials”790 This PSUR sub-section should summarise information relevant to the benefit-risk assessment of the791 medicinal product from other clinical trial/study sources, including patient support programs, which are792 accessible by the marketing authorisation holder during the reporting interval (e.g. results from pool793 analysis or meta-analysis of randomised clinical trials, safety information provided by co-development794 partners or from investigator-initiated trials).795 VII.B.5.9 2. PSUR sub-section “Medication errors”796 This sub-section should summarise relevant information on patterns of medication errors and potential797 medication errors, even when not associated with adverse outcomes. A potential medication error is798 the recognition of circumstances that could lead to a medication error, and may or may not involve a799 patient. Such information may be relevant to the interpretation of safety data or the overall benefit-800 risk evaluation of the medicinal product. A medication error may arise at any stage in the medication801 use process and may involve patients, consumers, or healthcare professionals.802 VII.B.5.10. PSUR section “Non-clinical data”803 This PSUR section should summarise major safety findings from non-clinical in vivo and in vitro studies804 (e.g. carcinogenicity, reproduction or immunotoxicity studies) ongoing or completed during the805 reporting interval. Results from studies designated to address specific safety concerns should be806
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 23/69 included in the PSUR, regardless of the outcome. Implications of these findings should be discussed in807 the relevant evaluation sections of the PSUR.808 VII.B.5.11. PSUR section “Literature”809 This PSUR section should include a summary of new and significant safety findings, either published in810 the peer-reviewed scientific literature or made available as unpublished manuscripts that the811 marketing authorisation holder became aware of during the reporting interval, when relevant to the812 medicinal product.813 Literature searches for PSURs should be wider than those for individual adverse reaction cases as they814 should also include studies reporting safety outcomes in groups of subjects and other products815 containing the same active substance.816 The special types of safety information that should be included, but which may not be found by a817 search constructed specifically to identify individual cases, include:818  pregnancy outcomes (including termination) with no adverse outcomes;819  use in paediatric populations;820  compassionate supply, named patient use;821  lack of efficacy;822  asymptomatic overdose, abuse or misuse;823  medication error where no adverse events occurred;824  important non-clinical safety results.825 If relevant and applicable, information on other active substances of the same class should be826 considered.827 The publication reference should be provided in the style of the Vancouver Convention13,14 .828 VII.B.5.12. PSUR section “Other periodic reports”829 This PSUR section will only apply in certain circumstances concerning fixed combination products or830 products with multiple indications and/or formulations where multiple PSURs are prepared in831 agreement with the competent authority. In general, the marketing authorisation holder should832 prepare a single PSUR for a single active substance (unless otherwise specified by the competent833 authority); however if multiple PSURs are prepared for a single medicinal product, this section should834 also summarise significant findings from other PSURs if they are not presented elsewhere within the835 report.836 When available, based on the contractual agreements, the marketing authorisation holder should837 summarise significant findings from periodic reports provided during the reporting interval by other838 parties (e.g. sponsors, other marketing authorisation holders or other contractual partners).839 13 Uniform requirements for manuscripts submitted to biomedical journals. International Committee of Medical Journal Editors. N Engl J Med. 1997 Jan 23;336(4):309-15. Available online: http://www.nejm.org/doi/full/10.1056/NEJM199701233360422 14 Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication [Updated April 2010] Publication Ethics: Sponsorship, Authorship, and Accountability, International Committee of Medical Journal Editors. http://www.icmje.org/urm_full.pdf
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 24/69 VII.B.5.13. PSUR section “Lack of efficacy in controlled clinical trials”840 This section should summarise data from clinical trials indicating lack of efficacy or lack of efficacy841 relative to established therapy(ies) for products intended to treat or prevent serious or life-threatening842 illnesses (e.g. excess cardiovascular adverse events in a trial of a new anti-platelet medicine for acute843 coronary syndromes) that could reflect a significant risk to the treated population.844 VII.B.5.14. PSUR section “Late-breaking information”845 The marketing authorisation holder should summarise in this PSUR section the potentially important846 safety, efficacy and effectiveness findings that arise after the data lock point but during the period of847 preparation of the PSUR. Examples include clinically significant new publications, important follow-up848 data, clinically relevant toxicological findings and any action that the marketing authorisation holder, a849 data monitoring committee, or a competent authority (worldwide) has taken for safety reasons. New850 individual case reports should not be routinely included unless they are considered to constitute an851 important index case (i.e. the first instance of an important event) or an important safety signal or852 where they may add information to the evaluation of safety concerns already presented in the PSUR853 (e.g. a well documented case of aplastic anaemia in a medicinal product known to be associated with854 adverse effects on the bone marrow in the absence of possible alternative causes).855 Any significant change proposed to the reference product information (e.g. new adverse reaction,856 warning or contraindication) which has occurred during this period, should also be included in this857 section of the PSUR (see VII.B.4.), where feasible.858 The data presented in this section should also be taken into account in the evaluation of risks and new859 information (see VII.B.5.16.3.).860 VII.B.5.15. PSUR section “Overview of signals: new, ongoing, or closed”861 The general location for presentation of information on signals and risks within the PSUR is shown in862 figure 1 (see VII.B.21.). The purpose of this section is to provide a high level overview of signals15 that863 were closed (i.e., evaluation was completed) during the reporting interval as well as ongoing signals864 that were undergoing evaluation at the end of the reporting interval. For the purposes of the PSUR, a865 signal should be included once it has undergone the initial screening or clarification step, and a866 determination made to conduct further evaluation by the marketing authorisation holder16 .It should be867 noted that a safety signal is not synonymous with a statistic of disproportionate reporting for a specific868 medicine/event combination as a validation step is required. Signals may be qualitative (e.g., a pivotal869 individual case safety report, case series) or quantitative (e.g. a disproportionality score, findings of a870 clinical trial or epidemiological study). Signals may arise in the form of an information request or871 inquiry on a safety issue from a competent authority (worldwide) (see Module IX).872 Decisions regarding the subsequent classification of these signals and the conclusions of the873 evaluation, involve medical judgement and scientific interpretation of available data, which is874 presented in section 16 (“Signal and risk evaluation”) of the PSUR.875 A new signal refers to a signal that has been identified during the reporting interval. Where new876 clinically significant information on a previously closed signal becomes available during the reporting877 interval of the PSUR, this would also be considered a new signal on the basis that a new aspect of a878 15 “Signal” means information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action [IR Art 19(1)]. 16 In the EU-regulatory network and for the purpose of the PSUR, the term “signal” in this section corresponds with the term “validated signal” described in GVP Module IX
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 25/69 previously refuted signal or recognised risk warrants further action to verify. New signals may be879 classified as closed or ongoing, depending on the status of signal evaluation at the end of the reporting880 interval of the PSUR.881 Examples of new signals would therefore include new information on a previously:882  Close and refuted signal, which would result in the signal being re-opened.883  Identified risk where the new information suggests a clinically significant difference in the severity884 or frequency of the risk (e.g. transient liver enzyme increases are identified risks and new885 information indicative of a more severe outcome such as hepatic failure is received, or neutropenia886 is an identified risk and a well documented case report of agranulocytosis with no presence of887 possible alternative causes is received).888  Identified risk for which a higher frequency or severity of the risk is newly found (e.g. in an889 indicated subpopulation).890  Potential risk which, if confirmed, would warrant a new warning, precaution, a new contraindication891 or restriction in indication(s) or population or other risk minimisation activities.892 Within this section, or as an appendix the marketing authorisation holder should provide a tabulation893 of all signals ongoing or closed at the end of the reporting interval. This tabulation should include the894 following information:895  a brief description of the signal;896  date when the marketing authorisation holder became aware of the signal;897  status of the signal at the end of the reporting interval (close or ongoing);898  date when the signal was closed, if applicable;899  source of the signal;900  a brief summary of the key data;901  plans for further evaluation; and902  actions taken or planned.903 And example of tabulation of signals can be found in VII. Appendix 2.904 The detailed signal assessments for closed signals are not to be included in this section but instead905 should be presented in sub-section 16.2 (“Signal evaluation”) of the PSUR.906 Evaluation of new information in relation to any previously known identified and potential risks and not907 considered to constitute a new signal should be provided in PSUR sub-section 16.3 (“Evaluation of risks908 and new information”).909 When a competent authority (worldwide) has requested that a specific topic (not considered a signal)910 be monitored and reported in a PSUR, the marketing authorisation holder should summarise the result911 of the analysis in this section if it is negative. If the specific topic becomes a signal, it should be912 included in the signal tabulation and discussed in sub-section 16.2 (“Signal evaluation”).913 VII.B.5.16. PSUR section “Signal and risk evaluation”914 The purpose of this section of the PSUR is to provide:915
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 26/69  A succinct summary of what is known about important identified and potential risks and important916 missing information at the beginning of the reporting interval covered by the report917 (VII.B.5.16.1.).918  An evaluation of all signals closed during the reporting interval (VII.B.5.16.2.).919  An evaluation of new information with respect to previously recognised identified and potential920 risks (VII.B.5.16.3).921  An updated characterisation of important potential and identified risks, where applicable922 (VII.B.5.16.4.).923  A summary of the effectiveness of risk minimisation activities in any country or region which may924 have utility in other countries or regions (VII.B.5.16.5.).925 A flowchart illustrating the mapping of signals and risks to specific sections/sub-sections of the PSUR926 can be found in VII.B.5.21..927 These evaluation sub-sections should not summarise or duplicate information presented in previous928 sections of the PSUR but should rather provide interpretation and critical appraisal of the information,929 with a view towards characterising the profile of those risks assessed as important. In addition, as a930 general rule, it is not necessary to include individual case narratives in the evaluation sections of the931 PSUR but where integral to the scientific analysis of a signal or risk, a clinical evaluation of pivotal or932 illustrative cases (e.g. the first case of suspected agranulocytosis with an active substance belonging to933 a class known to be associated with this adverse reaction) should be provided (see VII.B.3.).934 VII.B.5.16.1. PSUR sub-section “Summary of safety concerns”935 The purpose of this sub-section is to provide a summary of important safety concerns at the beginning936 of the reporting interval, against which new information and evaluations can be made. For products937 with an existing safety specification, this section can be either the same as, or derived from the safety938 specification summary17 that is current at the start of the reporting interval of the PSUR. It should939 provide the following safety information:940  important identified risks;941  important potential risks; and942  important missing information.943 The following factors should be considered when determining the importance of each risk:944  medical seriousness of the risk, including the impact on individual patients;945  its frequency, predictability, preventability, and reversibility;946  potential impact on public health (frequency; size of treated population); and947  potential for avoidance of the use of a medicinal product with a preventive benefit due to a948 disproportionate public perception of risk (e.g. vaccines).949 For products without an existing safety specification, this section should provide information on the950 important identified and potential risks and important missing information associated with use of the951 product, based on pre- and post-authorisation experience. Important identified and potential risks may952 include, for example:953  important adverse reactions;954 17 ICH-E2E – Pharmacovigilance planning (see Annex IV).
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 27/69  interactions with other medicinal products;955  interactions with foods and other substances;956  medication errors;957  effects of occupational exposure; and958  pharmacological class effects.959 The summary on important missing information should take into account whether there are critical960 gaps in knowledge for specific safety issues or populations that use the medicinal product.961 VII.B.5.16.2. PSUR sub-section “Signal evaluation”962 This sub-section of the PSUR should summarise the results of evaluations of all safety signals (whether963 or not classified as important) that were closed during the reporting interval. A safety signal can be964 closed either because it is refuted or because it is determined to be a potential or identified risk,965 following evaluation. The two main categories to be included in this sub-section are:966 1. Those signals that, following evaluation, have been refuted as “false” signals based on medical967 judgement and scientific evaluation of the currently available information.968 2. Those signals that, following evaluation, have been categorised as either a potential or identified969 risk, including lack of efficacy.970 For both categories of closed signals, a concise description of each signal evaluation should be included971 in order to clearly describe the basis upon which the signal was either refuted or considered to be a972 potential or identified risk by the marketing authorisation holder.973 It is recommended that the level of detail provided in the description of the signal evaluation should974 reflect the medical significance of the signal (e.g. severe, irreversible, lead to increased morbidity or975 mortality) and potential public health importance (e.g. wide usage, frequency, significant use outside976 the recommendations of the product information) and the extent of the available evidence. Where977 multiple evaluations will be included under both categories of closed signals, they can be presented in978 the following order:979  Closed and refuted signals.980  Closed signals that are categorised as important potential risks.981  Closed signals that are categorised as important identified risks.982  Closed signals that are potential risks not categorised as important.983  Closed signals that are identified risks not categorised as important.984 Where applicable the evaluations of closed signals can be presented by indication or population.985 The description(s) of the signal evaluations can be included in this sub-section of the PSUR or in an986 appendix. Each evaluation should include the following information as appropriate:987  source or trigger of the signal;988  background relevant to the evaluation;989  method(s) of evaluation, including data sources, search criteria (where applicable, the specific990 MedDRA terms (e.g. PTs, HLTs, SOCs, etc.) or Standardised MedDRA Queries (SMQs) that were991 reviewed), and analytical approaches;992
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 28/69  results - a summary and critical analysis of the data considered in the signal evaluation; where993 integral to the assessment, this may include a description of a case series or an individual case994 (e.g. an index case of well documented agranulocytosis or Stevens Johnson Syndrome);995  discussion;996  conclusion.997 VII.B.5.16.3. PSUR sub-section “Evaluation of risks and new information”998 This sub-section should provide a critical appraisal of new information relevant to previously999 recognised risks that is not already included in sub-section 16.2 (“Signal evaluation”).1000 New information that constitutes a signal with respect to a previously recognised risk or previously1001 refuted signal should be presented in the signals tabulation (see VII.B.5.15.) and evaluated in sub-1002 section 16.2 (“Signal evaluation”), if the signal is also closed during the reporting interval of the PSUR1003 Updated information on a previously recognised risk that does not constitute a signal should be1004 included in this sub-section. Examples includes information that confirms a potential risk as an1005 identified risk,1006 or information which allows any other further characterisation of a previously recognised risk.1007 New information can be organised as follows:1008 1. New information on important potential risks.1009 2. New information on important identified risks.1010 3. New information on other potential risks not categorised as important.1011 4. New information on other identified risks not categorised as important.1012 5. Update on important missing information.1013 The focus of the evaluation(s) is on new information which has emerged during the reporting interval1014 of the PSUR. This should be concise and interpret the impact, if any, on the understanding and1015 characterisation of the risk. Where applicable, the evaluation will form the basis for an updated1016 characterisation of important potential and identified risks in sub-section 16.4 (“Characterisation of1017 risks”) of the report. It is recommended that the level of detail of the evaluation included in this sub-1018 section should be proportional to the available evidence on the risk and its medical significance and1019 public health relevance.1020 The evaluation(s) of the new information and missing information update(s) can be included in this1021 sub-section of the PSUR, or in an appendix. Each evaluation should include the following information as1022 appropriate:1023  source of the new information;1024  background relevant to the evaluation;1025  method(s) of evaluation, including data sources, search criteria, and analytical approaches;1026  results – a summary and critical analysis of the data considered in the risk evaluation;1027  discussion;1028  conclusion, including whether or not the evaluation supports an update of the characterisation of1029 any of the important potential and identified risks in sub-section 16.4 (“Characterisation of risks”)1030
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 29/69 Any new information on populations exposed or data generated to address previously missing1031 information should be critically assessed in this sub-section. Unresolved concerns and uncertainties1032 should be acknowledged.1033 VII.B.5.16.4. PSUR sub-section “Characterisation of risks”1034 This sub-section should characterise important identified and potential risks based on cumulative data1035 (i.e., not restricted to the reporting interval), and describe important missing information.1036 Depending on the nature of the data source, the characterisation of risk may include, where applicable:1037  frequency;1038  numbers of cases (numerator) and precision of estimate, taking into account the source of the1039 data;1040  extent of use (denominator) expressed as numbers of patients, patient-time, etc., and precision of1041 estimate;1042  estimate of relative risk and precision of estimate;1043  estimate of absolute risk and precision of estimate;1044  impact on the individual patient (effects on symptoms, quality or quantity of life);1045  public health impact;1046  patient characteristics relevant to risk (e.g. patient factors (age, pregnancy/lactation, hepatic/renal1047 impairment, relevant co-morbidity, disease severity, genetic polymorphism);1048  dose, route of administration;1049  duration of treatment, risk period;1050  preventability (i.e. predictability, ability to monitor for a “sentinel” adverse reaction or laboratory1051 marker);1052  reversibility;1053  potential mechanism; and1054  strength of evidence and its uncertainties, including analysis of conflicting evidence, if applicable.1055 When missing information could constitute an important risk, it should be included as a safety concern.1056 The limitations of the safety database (in terms of number of patients studied, cumulative exposure or1057 long term use, etc.) should be discussed.1058 For PSURs for products with several indications, formulations, or routes of administration, where there1059 may be significant differences in the identified and potential risks, it may be appropriate to present1060 risks by indication, formulation, or route of administration. Headings that could be considered include:1061  risks relating to the active substance;1062  risks related to a specific formulation or route of administration (including occupational exposure);1063  risks relating to a specific population;1064  risks associated with non-prescription use (for compounds that are available as both prescription1065 and non-prescription products); and1066
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 30/69 VII.B.5.16.5. PSUR sub-section: “Effectiveness of risk minimisation (if applicable)”1067 Risk minimisation activities are public health interventions intended to prevent the occurrence of an1068 adverse drug reaction(s) associated with the exposure to a medicinal product or to reduce its severity1069 should it occur. The aim of a risk minimisation activity is to reduce the probability or severity of an1070 adverse drug reaction. Risk minimisation activities may consist of routine risk minimisation (e.g.1071 product labelling) or additional risk minimisation activities (e.g. Direct Healthcare Professional1072 Communication/educational materials).1073 The PSUR shall contain the results of assessments of the effectiveness of risk minimisation activities1074 relevant to the risk-benefit assessment [IR Art 34(3)].1075 Relevant information on the effectiveness and/or limitations of specific risk minimisation activities for1076 important identified risks that has become available during the reporting interval should be1077 summarised in this sub-section of the PSUR.1078 Insights into the effectiveness of risk minimisation activities in any country or region that may have1079 utility in other countries or regions are of particular interest. Information may be summarised by1080 region, if applicable and relevant.1081 When required for reporting in a PSUR, results of evaluations that became available during the1082 reporting interval, which refer to an individual region should be provided in the PSUR regional appendix1083 (see VII.B.5.20. and VII.C.5.5.).1084 VII.B.5.17. PSUR section “Benefit evaluation”1085 PSUR sub-sections 17.1 (“Important baseline efficacy and effectiveness information”) and 17.2 (“Newly1086 identified information on efficacy and effectiveness”) provide the baseline and newly identified benefit1087 information that support the characterisation of benefit described in sub-section 17.31088 (“Characterisation of benefits”) that in turn supports the benefit-risk evaluation in section 181089 (“Integrated benefit-risk analysis for authorised indications”).1090 VII.B.5.17.1. PSUR sub-section “Important baseline efficacy and effectiveness information”1091 This sub-section of the PSUR summarises information on both efficacy and effectiveness of the1092 medicinal product at the beginning of the reporting interval and provides the basis for the benefit1093 evaluation. This information should relate to authorised indication(s) of the medicinal product listed in1094 the reference product information (See VII.B.4.) .1095 For medicinal products with multiple indications, populations, and/or routes of administration, the1096 benefit should be characterised separately by these factors when relevant.1097 The level of detail provided in this sub-section should be sufficient to support the characterisation of1098 benefit in the PSUR sub-section 17.3 (“Characterisation of benefits”) and the benefit-risk assessment1099 in section 18 (“Integrated benefit-risk analysis for authorised indications”).1100 VII.B.5.17.2. PSUR sub-section “Newly identified information on efficacy and effectiveness”1101 For some products, additional information on efficacy or effectiveness in authorised indications may1102 have become available during the reporting interval. Such information should be presented in this sub-1103 section of the PSUR. For authorised indications, new information on efficacy and effectiveness under1104 conditions of actual use should also be described in this sub-section, if available. New information on1105 efficacy and effectiveness in uses other than the authorised indications should not be included unless1106 relevant for the benefit-risk evaluation in the authorised indications.1107
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 31/69 Information on indications newly authorised during the reporting interval should also be included in1108 this sub-section. The level of detail provided in this section should be sufficient to support the1109 characterisation of benefit in sub-section 17.3 (“Characterisation of benefits”) and the benefit-risk1110 assessment in section 18 (“Integrated benefit-risk analysis for authorised indications”).1111 In this sub-section, particular attention should be given to vaccines, anti-infective agents or other1112 medicinal products where changes in the therapeutic environment may impact on1113 efficacy/effectiveness over time.1114 VII.B.5.17.3. PSUR sub-section “Characterisation of benefits”1115 This sub-section provides an integration of the baseline benefit information and the new benefit1116 information that has become available during the reporting interval, for authorised indications.1117 The level of detail provided in this sub-section should be sufficient to support the analysis of benefit-1118 risk in section 18 (“Integrated benefit-risk analysis for authorised indications”).1119 When there are no new relevant benefit data, this sub-section should provide a characterisation of the1120 information in sub-section 17.1 (“Important baseline efficacy and effectiveness information”).1121 When there is new positive benefit information and no significant change in the risk profile in this1122 reporting interval, the integration of baseline and new information in this sub-section should be1123 succinct.1124 This sub-section should provide a concise but critical evaluation of the strengths and limitations of the1125 evidence on efficacy and effectiveness, considering the following when available:1126  a brief description of the strength of evidence of benefit, considering comparator(s), effect size,1127 statistical rigor, methodological strengths and deficiencies, and consistency of findings across1128 trials/studies;1129  new information that challenges the validity of a surrogate endpoint, if used;1130  clinical relevance of the effect size;1131  generalisability of treatment response across the indicated patient population (e.g. information that1132 demonstrates lack of treatment effect in a sub-population);1133  adequacy of characterization of dose-response;1134  duration of effect;1135  comparative efficacy; and1136  a determination of the extent to which efficacy findings from clinical trials are generalisable to1137 patient populations treated in medical practice.1138 VII.B.5.18. PSUR section “Integrated benefit-risk analysis for authorised1139 indications”1140 The marketing authorisation holder should provide in this PSUR section an overall appraisal of the1141 benefit and risk of the medicinal product as used in clinical practice. Whereas sub-sections 16.41142 (“Characterisation of risks”) and 17.3 (“Characterisation of benefits”) present the risks and benefits,1143 this section should provide a critical analysis and integration of the key information in the previous1144 sections and should not simply duplicate the benefit and risk characterisation presented in the sub-1145 sections mentioned above.1146
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 32/69 VII.B.5.18.1. PSUR sub-section “Benefit-risk context - medical need and important1147 alternatives”1148 This sub-section of the PSUR should provide a brief description of the medical need for the medicinal1149 product in the authorised indications and summarised alternatives (medical, surgical or other;1150 including no treatment).1151 VII.B.5.18.2. PSUR sub-section “Benefit-risk analysis evaluation”1152 A risk-benefit balance is specific to an indication and population. Therefore, for products authorised for1153 more than one indication, risk-benefit balancess should be evaluated and presented by each indication1154 individually. If there are important differences in the risk-benefit balance among populations within an1155 indication, the benefit-risk evaluation should be presented by population, if possible.1156 The benefit-risk evaluation should be presented and discussed in a way that facilitates the comparison1157 of benefits and risks and should take into account the following points :1158  Whereas previous sections/sub-sections should include all important benefit and risk information,1159 not all benefits and risks contribute importantly to the overall benefit-risk evaluation, therefore,1160 the key benefits and risks considered in the evaluation should be specified. The key information1161 presented in the previous benefit and risk section/sub-sections should be carried forward for1162 integration in the benefit-risk evaluation.1163  Consider the context of use of the medicinal product: the condition to be treated, prevented, or1164 diagnosed; its severity and seriousness; and the population to be treated (relatively healthy;1165 chronic illness, rare conditions).1166  With respect to the key benefit(s), consider its nature, clinical importance, duration, and1167 generalisability, as well as evidence of efficacy in non-responders to other therapies and alternative1168 treatments. Consider the effect size. If there are individual elements of benefit, consider all (e.g.1169 for therapies for rheumatoid arthritis: reduction of symptoms and inhibition of radiographic1170 progression of joint damage).1171  With respect to risk, consider its clinical importance, (e.g. nature of toxicity, seriousness,1172 frequency, predictability, preventability, reversibility, impact on patients), and whether it arose1173 from clinical trials in unauthorised indications or populations, off-label use, or misuse.1174  The strengths, weaknesses, and uncertainties of the evidence should be considered when1175 formulating the benefit-risk evaluation. Describe how uncertainties in the benefits and risks impact1176 the evaluation. Limitations of the assessment should be discussed.1177 Provide a clear explanation of the methodology and reasoning used to develop the benefit-risk1178 evaluation:1179  The assumptions, considerations, and judgement or weighting that support the conclusions of the1180 benefit-risk evaluation should be clear.1181  If a formal quantitative or semi-quantitative assessment of benefit-risk is provided, a summary of1182 the methods should be included.1183  Economic considerations (e.g. cost-effectiveness) should not be considered in the benefit-risk1184 evaluation.1185 When there is important new information or an ad hoc PSUR has been requested, a detailed benefit-1186 risk analysis should be presented based on cumulative data . Conversely, where little new information1187
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 33/69 has become available during the reporting interval, the primary focus of the benefit-risk evaluation1188 might consist of an evaluation of updated interval safety data.1189 VII.B.5.19. PSUR section “Conclusions and actions”1190 A PSUR should conclude with the implications of any new information that arose during the reporting1191 interval in terms of the overall evaluation of benefit-risk for each authorised indication, as well as for1192 relevant subgroups, if appropriate.1193 Based on the evaluation of the cumulative safety data and the benefit-risk analysis, the marketing1194 authorisation holder should assess the need for changes to the reference product information and1195 propose changes as appropriate.1196 In addition and as applicable, the conclusions should include preliminary proposal(s) to optimise or1197 further evaluate the risk-benefit balance for further discussion with the relevant competent1198 authority(ies). This may include proposals for additional risk minimisation activities.1199 For products with a pharmacovigilance or risk management plan, the proposals should also be1200 considered for incorporation into the pharmacovigilance plan and/or risk minimisation plan, as1201 appropriate (see Module V).1202 Based on the evaluation of the cumulative safety data and the risk-benefit analysis, the marketing1203 authorisation holder shall draw conclusions in the PSUR as to the need for changes and/or actions,1204 including implications for the approved summary of product characteristics (SmPC) for the product(s)1205 for which the PSUR is submitted [IR Art 34(5)]. The regional appendix should include proposals for1206 product information (SmPC and package leaflet) together with information on ongoing changes when1207 applicable.1208 VII.B.5.20. Appendices to the PSUR1209 A PSUR should contain the following appendices as appropriate, numbered as follows:1210 1. Reference information(see VII.B.4.).1211 2. Cumulative summary tabulations of serious adverse events from clinical trials; and cumulative and1212 interval summary tabulations of serious and non-serious adverse reactions from post-marketing1213 data sources.1214 3. Tabular summary of safety signals (if not included in the body of the report)18 .1215 4. Listing of all the marketing authorisation holder-sponsored interventional and non-interventional1216 studies with the primary aim of identifying, characterising, or quantifying a safety hazard or1217 confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk1218 management measures, in case of non-interventional studies.1219 5. List of the sources of information used to prepare the PSUR (when desired by the marketing1220 authorisation holder).1221 6. Regional appendix:1222 The requirements for the regional appendix in the EU are provided in section VII.C.5..1223 1224 18 It is preferred to include the tabulation of signals in the body of the PSUR, if feasible.
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 34/69 VII.B.5.21. Mapping signals and risks to PSUR sections/sub-sections1225 The following flowchart (Figure VII.1) reflects the general location for the presentation of information1226 on signals and risks within the PSUR.1227 Figure VII.1. PSUR Sections/subsections – signals and risks.1228 Key to benefit-risk evaluation? Safety data from available information sources Previously recognised risk? New information constituting a signal? Yes Safety signal detected? No No further documentation in the PSUR No Safety signal Section 15 Yes Close? Safety signal ongoing Section 15 Section 16.2 Yes Potential or Identified risk Important? Section 16.4 Yes Section 18.2 Yes Section 19 Consider update to E2E document, if applicable. Update RSI as appropriate No further documentation in the PSUR No Action(s) Proposed? No Yes Refuted signal No Section 16.3 New information on previously recognised identified/potential risk or missing information No No Yes 1229
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 35/69 VII.B.6. Quality systems for PSURs at the level of marketing authorisation1230 holders1231 Marketing authorisation holders should have in place structures and processes for the preparation,1232 quality control, review and submission of PSURs including follow-up during and after their assessment.1233 These structures and processes should be described by means of written policies and procedures in the1234 marketing authorisation holder’s quality system (see Module I).1235 There are a number of areas in the pharmacovigilance process that can directly impact the quality of1236 PSURs, some examples are case management of spontaneous and study reports, literature screening,1237 signal management, additional pharmacovigilance and post-marketing research activities, procedures1238 for integration of information on benefits and risks from all available data sources and maintenance of1239 product information. The quality system should describe the links between the processes, the1240 communication channels and the responsibilities with the aim of gathering all the relevant information1241 for the production of PSURs. There should be documented procedures including quality control checks1242 in place to check the accuracy and completeness of the data presented in the PSURs. In ensuring1243 completeness of data, a documented template or plan for drawing data from various data sources1244 could be developed. The importance of an integrated approach to benefit-risk evaluation should1245 underpin processes and cross departmental input to PSUR preparation.1246 The PSUR should also contain the assessment of specific safety issues requested to be addressed in the1247 PSUR by competent authorities (worldwide). The marketing authorisation holder should have1248 mechanisms in place to ensure that the requests made by competent authorities (worldwide) during1249 the time of their PSUR assessment are properly addressed.1250 The provision of the data included in the summary tabulations (see VII.B.5.6.) should undergo source1251 data verification against the marketing authorisation holder’s safety database to ensure accuracy of the1252 number of events/reactions provided. The process for querying the safety database, the parameters1253 used for the retrieval of the data and the quality control performed should be properly documented.1254 An appropriate quality system should be in place in order to avoid failure to comply with PSUR1255 requirements such as:1256  non-submission: complete non-submission of PSURs, submission outside the correct submission1257 schedule or outside the correct time frames (without previous agreement with the competent1258 authorities);1259  unjustified omission of information required by VII.B.5.;1260  poor quality reports: poor documentation or insufficient information or evaluation provided to1261 perform a thorough assessment of the new safety information, signals, risk evaluation, benefit1262 evaluation and integrated benefit-risk analysis, misuse not highlighted, absence of use of1263 standardised medical terminology (e.g. MedDRA) and inappropriate dismissal of cases with no1264 reported risk factors in cumulative reviews;1265  submission of a PSUR where previous requests from competent authorities (worldwide) have not1266 been addressed.1267  failure to provide an explicit evaluation of the risk-benefit balance of the medicinal product;1268  failure to provide adequate proposals for the local authorised product information.1269 Any significant deviation from the procedures relating to the preparation or submission of PSURs1270 should be documented and the appropriate corrective and preventive action should be taken. This1271 documentation should be available at all times.1272
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 36/69 When marketing authorisation holders are involved in contractual arrangements (e.g. licensor-1273 licensee), respective responsibilities for preparation and submission of the PSUR to the competent1274 authorities (worldwide) should be clearly specified in the written agreement.1275 When the preparation of the PSUR is delegated to third parties, the marketing authorisation holder1276 should ensure that they are subject to a quality system compliant with the current legislation. Explicit1277 procedures and detailed agreements should exist between the marketing authorisation holder and third1278 parties. The agreements may specifically detail the options to audit the PSUR preparation process.1279 VII.B.7. Training of staff members related to the PSUR process1280 For all organisations, it is the responsibility of the person responsible for the pharmacovigilance system1281 to ensure that the personnel, including pharmacovigilance, medical and quality personnel involved in1282 the preparation, review, quality control, submission and assessment of PSURs are adequately qualified,1283 experienced and trained according to the applicable guidelines (e.g. ICH E2C(R2) and this GVP Module1284 VII). When appropriate, specific training for the different processes, tasks and responsibilities relating1285 to the PSUR should be in place.1286 Training to update knowledge and skills should also take place as necessary.1287 Training should cover legislation, guidelines, scientific evaluation and written procedures related to the1288 PSUR process. Training records should demonstrate that the relevant training was delivered prior to1289 performing PSUR-related activities.1290 VII.C. Operation of the EU network1291 VII.C.1. PSUR process in the EU - General process1292 The following flowchart (Figure VII.2.) reflects the general process cycle for the PSUR procedure at the1293 EU level when recommendations by the PRAC are issued. This represents a high level cycle to outline1294 the entire process, from the preparation of the report to the implementation of the European1295 Commission decision/national actions when applicable. Different single steps in this flowchart are1296 formed by intermediate steps further explained and developed in different sections in this Module.1297
Guideline on good pharmacovigilance practices (GVP) – Module VII EMA/252670/20122 Page 37/69 Figure VII.2. PSUR procedure - general process1298 1299 1300 MAH (10) PSUR creation EMA PSUR Repository PSUR 70/90 days PSUR PSUR available to Stakeholders NCAs, PRAC, CHMP, CMD(h), EC MA, EURD list, Standard PSUR submission schedule* PRAC Rapporteur or MS PSUR PRAC, CMDh Appointment of PRAC Rapporteur or MS EMA PSUR Repository 60 days PSUR PrAR available to Stakeholders NCAs, PRAC, CHMP, CMD(h), EC MAH (10) EMA PSUR Repository 30 days PRAC Rapporteur or MS 15 days PRAC CHMP PRAC Recommendation CMDh EMA PSUR Repository CHMP opinion CAP ± NAP If regulatory action is required NAPs Only If regulatory action is required DLP and frequency of Submission Comments PSUR PrAR PSUR PrAR EMA PSUR Repository PSUR updated AR Abbreviations used in this flowchart: MA: Marketing Authorisation MS: Member State EURD: European Union Reference Dates DLP: Data Lock Point MAH: Marketing Authorisation Holder NCA: National Competent Authorities CMD(h): Coordination Group for Mutual Recognition and Decentralised Procedures – Human PRAC: Pharmacovigilance and Risk Assessment Committee CHMP: Committee for Medicinal Products for Human use EC: European Commission PrAR: Preliminary Assessment Report AR: Assessment report CAP: Centrally authorised Product NAP: Nationally Authorised Product (including mutual recognition and decentralised procedure) *Standard PSUR submission schedule refers to 6 months, 1 year or 3 years as established in Directive 2001/83/EC Article 107C (2) 2nd paragraph. Next PRAC Meeting Legal references: 1 - [REG Art 28(2)] 2 - [DIR Art 107e(1)], [REG Art 28(3), 1st paragraph] 3 - [DIR Art 107e(2), 1st paragraph]. [REG Art 28(3), 2nd paragraph] 4 - [DIR Art 107e(2), 2nd paragraph], [REG Art 28(3), 3rd paragraph] 5 - [DIR Art 107e(3)], [REG Art 28(3), 4th paragraph] 6 - [DIR Art 107g(1) & (2), 1st paragraph)] 7 - [DIR Art 107g(3)], [REG Art 28(4)] 8 - [DIR Art 107g(4), [REG Art 28(4), 2nd paragraph & (5)] 9 - [DIR Art 107g(2), 3rd paragraph] 10 - [DIR Art 23(3)], [REG Art 16(3)] Repository: 1 - [REG Art 25a] 5 - [DIR Art 107e(3)], [REG Art 28(3), 4th paragraph] 3 4 5 6 7 8 9 PSUR updated AR EC EC No Agreement by consensus The MAH shall ensure that the product information is kept up to date with the current scientific knowledge, including the conclusions of the assessment and recommendations made public by means of the European medicines web-portal. 10 EC Decision CAPs National implementation NAPs only 2 National implementation Agreement by consensus CMDh Position MAH (10) MAH (10) MAH (10) 1301 1302 1303 1304 1305
Guideline on good pharmacovigilance practices (GVP) – Module VII EMA/252670/20122 Page 38/69 VII.C.2. Standard submission schedule of PSURs1306 Marketing authorisation holders for products authorised before 02 July 2012 (centrally authorised1307 products) and 21 July 2012 (nationally authorised products) and for which the frequency and dates of1308 submission of PSURs are not laid down as a condition to the marketing authorisation or determined1309 otherwise in the list of Union reference dates shall submit PSURs according to the following submission1310 schedule (hereafter “standard” submission schedule) [REG 28(2), DIR Art 107c(2)]:1311  at 6 months intervals once the product is authorised, even if it is not marketed;1312  once a product is marketed, 6 monthly PSUR submission should be continued following initial1313 placing on the market in the EU for 2 years, then once a year for the following 2 years and1314 thereafter at 3-yearly intervals.1315 VII.C.3. List of European Union reference dates and frequency of1316 submission of PSURs19 1317 VII.C.3.1. Objectives of the EU reference dates list1318 The Agency shall make public a list of Union reference dates (hereinafter referred to as list of EU1319 reference dates) and frequency of submission of PSURs by means of the European medicines web-1320 portal [DIR Art 107c(7), REG Art 26(1)(g)].1321 The objectives of the list of EU reference dates and frequency of submission of PSURs are:1322  Harmonisation of data lock point and frequency of submission of PSURs for the same active1323 substance and combination of active substances:1324 For medicinal products containing the same active substance or combination of active substances1325 subject to different marketing authorisations, an EU reference date should be set up and the1326 frequency and date of submission of PSURs harmonised in order to allow the preparation of a1327 single assessment established in DIR Art 107e(1). Such information should be included in the list1328 published by the Agency.1329  Optimisation of the management of PSURs and PSURs assessments within the EU:1330 The list overrules the submission schedule described in DIR Art 107c(2)(b).1331 For active substances or combinations of active substances included in the list, marketing1332 authorisation holders shall vary, if applicable, the condition laid down in their marketing1333 authorisations in order to allow the submission of PSURs in accordance to the frequency and1334 submission date as indicated in the list [DIR 107c(4) to (7)].1335 The periodicity is defined on the basis of a risk-based approach in order to prioritise the periodic1336 re-evaluation of the risk-benefit balance of active substances in a way that best protects public1337 health. [Directive 2010/84/EU Preamble Recital 23].1338  Single EU assessment and reassessment of the risk-benefit balance of an active substance based1339 on all available safety data:1340 The list enables the harmonisation of PSUR submissions for medicinal products containing the1341 same active substance or the same combination of active substances.1342 19 The initial EU reference dates list was adopted by the CHMP/CMDh following consultation of the PRAC in September 2012 and was published on 01 October 2012.
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 39/69 A single EU PSUR assessment provides a mechanism for evaluating the totality of available data on1343 the benefits and risks of an active substance or combination of active substances. The effective1344 application of work sharing principles is important in avoiding duplication of efforts and in1345 prioritising the use of limited resources in the best interests of European citizens.1346 VII.C.3.2. Description of the EU reference dates list1347 The Union reference date of medicinal products containing the same active substance or the same1348 combination of active substances shall be [DIR Art 107c(5)]:1349  the date of the first marketing authorisation in the EU of a medicinal product containing that active1350 substance or that combination of active substances; or1351  if the date of first marketing authorisation cannot be ascertained, the earliest of the known dates1352 of the marketing authorisations for a medicinal product containing that active substance or that1353 combination of active substances.1354 The list of EU reference dates and frequency of submission of PSURs consists of a comprehensive list of1355 substances and combinations of active substances in alphabetical order, for which PSURs, where1356 required, shall be submitted in accordance with the EU reference date and the frequency as1357 determined by the Committee for Medicinal Products for Human Use (CHMP) and the Coordination1358 Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) following consultation1359 with the Pharmacovigilance and Risk Assessment Committee (PRAC) [DIR Art 107c(4) and (6)]. The1360 list should be updated in line with the “list of all medicinal products for human use authorised in the1361 Union” as referred to in REG Art 57(1)(b).1362 The EU reference dates list should contain the following information:1363  the EU reference dates;1364  the frequencies of submission of PSURs;1365  the data lock points of the next submissions of PSURs;1366  the date of publication (on the European Medicines web-portal) of the frequency for PSURs1367 submission and data lock point for each active substance and combination of active substances.1368 Any change to the dates of submission and frequency on PSURs specified in the marketing1369 authorisation shall take effect 6 months after the date of such publication [DIR Art 107c(7)]1370 Where specificity is deemed necessary, the list should include the scope of the PSUR and related EU1371 single assessment procedure (see VII.C.3.3.) such as:1372  whether or not it should cover all the indications of the substance or combination of active1373 substances;1374  whether or not it should cover all the formulations/routes of administration of the products1375 containing a substance or combination of active substances;1376  whether generic, well-established use, traditional herbal and homeopathic medicinal products shall1377 submit a PSUR due to a request from a competent authority or due to concerns relating to1378 pharmacovigilance data or due to the lack of PSURs relating to an active substance after the1379 marketing authorisation has been granted [DIR Art 107c(2) second subparagraph] (see1380 VII.C.3.3.2.).1381 1382
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 40/69 VII.C.3.3. Application of the list of EU reference dates to submission of1383 PSURs1384 VII.C.3.3.1. Submission of PSURs for medicinal products: general requirement1385 Figure VII.3. presents the various potential scenarios for the submission of a PSUR as a general1386 requirement.1387 Figure VII.3. Conditions for PSURs submission as general requirement1388 1389 Medicinal product Does the marketing authorisation include a condition on the frequency of PSURs submission? Is the substance or combination included in the EURD list? No Follow the frequency as indicated in DIR Art 107c(2) until a frequency is laid down in the marketing authorisation or the substance (or combination) is included in the EURD list No Is the substance or combination included in the EURD list? Yes Follow the frequency as laid down in the marketing authorisation No If applicable, variation of the marketing authorisation to update the frequency as published in the EURD list Yes Follow the frequency as indicated in the EURD list Yes 1390
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 41/69 The data lock points included in the list of EU references dates enable the synchronisation of PSURs1391 submission for products subject to different marketing authorisations and permit the EU single1392 assessment. These data lock points are fixed on a certain date of the month, and should be used to1393 determine the submission date (which has legal status) of the PSUR. Marketing authorisation holders1394 can request to amend those dates in accordance with section VII.C.3.5.2.1395 Unless otherwise specified in the list of EU reference dates and frequency of submission, or agreed with1396 competent authorities in Member States or the Agency, as appropriate, a single PSUR shall be1397 prepared for all medicinal products containing the same active substance and authorised for one1398 marketing authorisation holder. The PSUR shall cover all indications, routes of administration, dosage1399 forms and dosing regimens, irrespective of whether authorised under different names and through1400 separate procedures. Where relevant, data relating to a particular indication, dosage form, route of1401 administration or dosing regimen shall be presented in a separate section of the PSUR and any safety1402 concerns shall be addressed accordingly [IR Art 34(6)].1403 For medicinal products containing an active substance or a combination of active substances not1404 included in the EU reference dates list, PSURs shall be submitted according to the PSUR frequency1405 defined in the marketing authorisation or if not specified, in accordance with the submission schedule1406 specified in DIR Art 107c(2) and REG Art 28(2).1407 VII.C.3.3.2. Submission of PSURs for generic, well-established use, traditional herbal and1408 homeopathic medicinal products1409 By way of derogation, generics (authorised under DIR Art 10(1)), well-established use (authorised1410 under DIR Art 10a), homeopathic (authorised under DIR Art 14) and traditional herbal (authorised1411 under DIR Art 16a) medicinal products are exempted from submitting PSURs except in the following1412 circumstances [DIR Art 107b(3)]:1413  the marketing authorisation provides for the submission of PSURs as a condition;1414  PSURs is (are) requested by a competent authority in a Member State on the basis of concerns1415 relating to pharmacovigilance data or due to the lack of PSURs relating to an active substance after1416 the marketing authorisation has been granted (e.g. when the “reference” medicinal product is no1417 longer marketed). The assessment reports of the requested PSURs shall be communicated to the1418 PRAC, which shall consider whether there is a need for a single assessment report for all marketing1419 authorisations for medicinal products containing the same active substance and inform the CMDh1420 or CHMP accordingly, in order to apply the procedures laid down in DIR Art 107c(4) and 107e.1421 In order to facilitate and optimise the PSUR EU single assessment process, to avoid duplications of1422 requests for PSURs and to provide transparency and predictability for the marketing authorisation1423 holders, the legislative provision laid down in DIR 107b(3)(b) is applied by specifying in the list of EU1424 reference dates, the substances for which PSURs for generic, well-established use, traditional herbal1425 and homeopathic medicinal products are required. This specification is based on the request made by a1426 competent authority in a Member State during the creation or maintenance of the list of EU reference1427 dates and on the basis of concerns relating to pharmacovigilance data or due to the lack of PSURs1428 relating to an active substance.1429 The harmonised frequency for the submission of the reports and the EU reference dates are1430 determined by the CHMP and/or CMDh after consultation of the PRAC.1431 The application of the list of EU reference dates for the submission of PSURs for generic, well-1432 established use, traditional herbal and homeopathic medicinal products does not undermine the right1433 of a competent authority in a Member State to request the submission of PSURs at any time under the1434 provision laid down in [DIR Art 107c(2) second subparagraph].1435
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 42/69 For products where PSURs are no longer required to be submitted routinely, it is expected that1436 marketing authorisation holders will continue to evaluate the safety of their products on a regular basis1437 and report any new safety information that impacts on the risk-benefit balance or the product1438 information (See Module VI and Module IX).1439 Figure VII.4. presents the various potential scenarios as regard the submission of a PSUR for generic,1440 well-established use, traditional herbal and homeopathic medicinal products:1441 Figure VII.4. Conditions for PSURs submission for generic, well-established use, traditional herbal1442 and homeopathic medicinal products1443 1444 Medicinal product Does the marketing authorisation include a condition on the frequency of PSURs submission? Is the substance or combination included in the EURD list? No No PSUR is required No Is the substance or combination included in the EURD list? Yes Follow the frequency as laid down in the marketing authorisation No If applicable, variation of the marketing authorisation to update the frequency as published in the EURD list Follow the frequency as indicated in the EURD list Are PSURs requested for generics, well-established use, traditional herbals or homeopathic?* Yes Are PSURs requested for generics, well-established use, traditional herbals or homeopathic?* Yes No Yes Yes No * Whether marketing authorisation holders for generics, well-established use, traditional herbal and homeopathic medicinal products are requested to submit PSURs following a request of a competent authority in a Member State due to concerns relating to pharmacovigilance data or lack of PSUR submission. 1445
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 43/69 VII.C.3.3.3. Submission of PSURs for fixed dose combination products1446 Unless otherwise specified in the list of EU reference dates and frequency of submission, if the1447 substance that is the subject of the PSUR is also authorised as a component of a fixed combination1448 medicinal product, the marketing authorisation holder shall either submit a separate PSUR for the1449 combination of active substances authorised for the same marketing authorisation holder with cross-1450 references to the single-substance PSUR(s), or provide the combination data within one of the single-1451 substance PSURs [IR Art 34(7)].1452 VII.C.3.3.4. Submission of PSURs on demand of a competent authority in a Member State1453 Marketing authorisation holders shall submit PSURs immediately upon request from a competent1454 authority in a Member State [DIR Art 107c(2)]. To facilitate the EU assessment and avoid duplication1455 requests, the competent authorities in the Member States should normally make use of the list of EU1456 reference dates to request the submission of PSURs, however in especial circumstances competent1457 authorities in Member States can directly request the submission of a PSUR. When the timeline for1458 submission has not been specified in the request, marketing authorisation holders should submit the1459 PSUR within 90 calendar days of the data lock point.1460 VII.C.3.4. Criteria used for defining the frequency of submission of PSURs1461 When deviating from the PSUR submission schedule defined in DIR Art 107c(2)(b), the frequencies of1462 submission of PSURs and the corresponding data lock points should be defined on a risk-based1463 approach by the CHMP where at least one of the marketing authorisations concerned has been granted1464 in accordance with the centralised procedure or by the CMDh otherwise, after consultation with the1465 PRAC.1466 The following prioritisation criteria should be taken into account when defining the frequency of1467 submission for a given active substance or combination of active substances:1468  information on risks or benefits that may have an impact on the public health;1469  new product for which there is limited safety information available to date (includes pre- and post-1470 authorisation experiences);1471  significant changes to the product (e.g. new indication has been authorised, new pharmaceutical1472 form or route of administration broadening the exposed patient population);1473  vulnerable patient populations/poorly studied patient populations, important missing information1474 (e.g. children, pregnant women) while these populations are likely to be exposed in the post-1475 authorisation setting;1476  signal of/potential for misuse, medication error, risk of overdose or dependency;1477  the size of the safety database and exposure to the medicinal product;1478  medicinal products subjected to additional monitoring.1479 Any change in the criteria listed above for a given active substance or combination of active substances1480 may lead to an amendment of the list of EU reference dates (e.g. increase of the frequency for PSUR1481 submission).1482
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 44/69 VII.C.3.5. Maintenance of the list of EU reference dates1483 VII.C.3.5.1. General principles1484 The maintenance of the list of EU reference dates should facilitate regulatory responsiveness to public1485 health concerns identified within the EU and therefore the list will be subject to changes to reflect the1486 decisions taken (e.g. by the Agency’s committees following signal detection).1487 The information included in the list such as the active substances and combinations of active1488 substances, the frequencies of submission of PSURs and data lock points may need to be updated1489 when considered necessary by the CHMP or CMDh after consultation with the PRAC. Changes to the list1490 may be applied on one of the following grounds:1491  emergence of new information that might have an impact on the risk-benefit balance of the active1492 substances or combinations of active substances, and potentially on public health;1493  any change in the criteria used for the allocation of frequency for PSUR submission and defined1494 under VII.C.3.4.;1495  a request from the marketing authorisation holders as defined under DIR Art 107c(6);1496  active substance newly authorised.1497 Figure VII.5. provides a general overview of the maintenance of the list of EU reference dates and1498 frequency of submission of PSURs1499
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 45/69 Figure VII.5. Maintenance of the list of EU reference dates and frequency of submission of PSUR1500 1501 Request for national competent authorities or marketing authorisation holders to determine the EU reference date or to change the frequency of PSURs submission Emergence of new safety information or change in the criteria used for the allocation of frequency of PSURs submission New Centrally Authorised product containing an active substance not included in the EURD list or included with a different frequency of PSURs submission CHMP/CMDh Scientific review and consideration by the PRAC For consultation PRAC recommendation on the amendment of the EURD list CHMP opinion/CMDh position Need to amend the EURD list? End No Publication of the amended EURD list in the European medicines web-portal Yes Where appropriate, marketing authorisation holders shall submit a variation to reflect the changes in their marketing authorisations 1502 1503
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 46/69 VII.C.3.5.2. Requests from marketing authorisation holders to amend the list of EU1504 reference dates1505 Marketing authorisation holders shall be allowed to submit a request to the CHMP or the CMDh, as1506 appropriate, to determine the Union reference dates or to change the frequency of submission of PSUR1507 on one of the following grounds [DIR Art 107c(6)]:1508  for reasons relating to public health;1509  in order to avoid a duplication of the assessment;1510  in order to achieve international harmonisation.1511 The request and its grounds should be considered by the PRAC and the CHMP if it concerns at least one1512 marketing authorisation granted in accordance with the centralised procedure or the CMDh otherwise,1513 which will either approve or deny the request.1514 The list will then be amended accordingly when appropriate and published on the European medicines1515 web-portal (see section VII.C.3.6.).1516 For details about how to submit requests for amendments to the list, refer to the EU reference dates1517 cover note and the related template published on the European medicines web-portal20 1518 VII.C.3.6. Publication of the list1519 Upon its establishment and adoption by the CHMP and CMDh following PRAC consultation, the list of EU1520 reference dates and frequency of submission of PSURs is published on the European medicines web-1521 portal.1522 In case of amendments, the updated list should be published following its adoption by the CHMP or the1523 CMDh. It is expected to be updated monthly.1524 VII.C.3.7. Amendment of the marketing authorisation according to the list1525 of EU reference dates1526 Any changes to the dates and frequencies of submission of PSURs specified in the list take effect six1527 months after the date of the publication on the European medicines web-portal Where appropriate,1528 marketing authorisation holders shall submit the relevant variation in order to reflect the changes in1529 their marketing authorisation [DIR 107c(6)], unless the marketing authorisation contains a direct cross1530 reference to the list of EU references dates. Where appropriate, marketing authorisation holders shall1531 submit the relevant variation in order to reflect the new information in their marketing authorisations1532 [DIR 107c(6)].1533 VII.C.4. Processes for PSUR Assessment in the EU network1534 The competent authorities in the Member States shall assess PSURs to determine whether there are1535 new risks or whether risks have changed or whether there are changes to the risk-benefit balance of1536 the medicinal product [DIR Art 107d].1537 For purely nationally authorised medicinal products authorised in one Member State, the assessment of1538 PSURs is conducted by the competent authority in the Member State where the product is authorised1539 (see VII.C.4.1.).1540 20 http://www.emea.europa.eu
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 47/69 For medicinal products authorised in more than one Member State (i.e. centrally authorised products,1541 products authorised through the mutual recognition and decentralised procedures) and for medicinal1542 products subject to different national marketing authorisations containing the same active substance or1543 the same combination of active substances whether or not held by the same marketing authorisation1544 holders and for which the frequency and dates of submission of PSURs have been harmonised in the1545 list of EU reference dates, an EU single assessment of all PSURs is conducted with recommendation1546 from the PRAC in accordance with the procedure described in VII.C.4.2.1. and VII.C.4.2.2..1547 Further to assessment of the PSUR and opinion from the CHMP or position from the CMDh, as1548 applicable, following the recommendation from the PRAC, the competent authorities in Member States,1549 or the European Commission for centrally authorised products, shall take the necessary measures to1550 vary, suspend or revoke the marketing authorisation(s), in accordance with outcome of the1551 assessment [DIR Art 107g(2)] [REG Art 28(4) and (5)] (see VII.C.4.2.3. and VII.C.4.2.4.).1552 The outcome of the PSUR assessment results in a legally binding decision or position in case of any1553 action to vary, suspend, revoke the marketing authorisations of the medicinal products containing the1554 concerned active substance or combination of active substances, on the basis of the position of the1555 CMDh or the opinion of the CHMP following the recommendations from the PRAC. Furthermore,1556 marketing authorisation holders are reminded of their obligation to keep their marketing authorisation1557 up to date in accordance with REG Art 16(3) and DIR Art 23(3). The recommendations are therefore1558 implemented in a harmonised and timely manner for all products within the scope of the procedure1559 across the EU.1560 Amendments to the SmPC, package leaflet and labelling as a result of the PSUR assessment should be1561 implemented without subsequent variation submission for centrally authorised products and through1562 the appropriate variation for nationally authorised products, including those authorised through the1563 mutual recognition and decentralised procedures.1564 When the proposals for the product information include new adverse reactions in section 4.81565 (“Undesirable effects”) of the SmPC, or modifications in the description, frequency and severity of the1566 existing reactions, marketing authorisation holders should provide in the PSUR detailed information to1567 allow the adequate description and classification of the frequency of the adverse reactions. If other1568 sections of the SmPC (e.g. SmPC section 4.4 “Special warnings and precautions for use”) are1569 considered to be updated, clear proposals should be provided for the competent authorities in the1570 Member States to consider during the PSUR assessment21 . The proposals should be included in the1571 PSUR regional appendix (VII.C.5.).1572 Harmonisation of the entire product information in all the Member States where the product is1573 authorised is not one of the objectives of the PSUR assessment procedure. Instead, the outcome of the1574 assessment should incorporate the new safety warnings and key risk minimisation recommendations,1575 arising from the assessment of the data in the PSUR, to be included in the relevant sections of the1576 product information.1577 VII.C.4.1. PSURs for purely nationally authorised medicinal products1578 It is the responsibility of the competent authority in the Member State where the product is authorised1579 to evaluate the PSURs for these medicinal products and the assessment is conducted in accordance1580 with the national legislation.1581 Listings of individual cases may be requested in the context of the PSUR assessment procedure for1582 adverse reactions of special interest and should be provided by the marketing authorisation holder1583 21 See “Guideline on Summary of Product Characteristics” as published on the Website of the European Commission in the Notice to Applicants, Volume 2C: http://ec.europa.eu/health/files/eudralex
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 48/69 within an established timeframe to be included in the request. This may be accompanied by a request1584 for an analysis of cases classified as non-serious.1585 Following the assessment of PSURs, the competent authority in the Member State should consider1586 whether any action concerning the marketing authorisation for the medicinal product concerned is1587 necessary. They should vary, suspend or revoke the marketing authorisation when applicable1588 according to the appropriate procedure at national level.1589 The assessment report and conclusions of the competent authority in the Member State should be1590 provided to the marketing authorisation holder.1591 VII.C.4.2. Medicinal products authorised in more than one Member State1592 VII.C.4.2.1. Assessment of PSURs for a single centrally authorised medicinal product1593 This section describes the assessment of PSURs where only one centrally authorised medicinal product1594 is involved according to the procedure set up in Article 28 of Regulation (EC) No 726/2004 (see figure1595 VII.6.).1596
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 49/69 Figure VII.6. PSUR assessment procedure for a single centrally authorised medicinal product1597 Receipt of PSUR(s) from MAH(s) Technical validation by the Agency Start Rapporteur preliminary assessment report 60 days Comments from MAH(s) and members of the PRAC 30 days Rapporteur updated assessment report 15 days PRAC recommendation At the next PRAC meeting PRAC recommendation received by CHMP If variation, suspension or revocation of the marketing authorisation is recommended CHMP opinion with timetable for implementation 30 days Opinion sent to EC, marketing authorisation holder and NCAs EC decision to update centralised marketing authorisation 1598
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 50/69 The assessment of PSURs for a single centrally authorised medicinal product is coordinated by the1599 Agency and shall be conducted by a Rapporteur appointed by the PRAC [REG Art 28(3)] (hereinafter1600 referred to as “PRAC Rapporteur”).1601 Upon receipt, the Agency should perform a technical validation of the report to ensure that the PSUR1602 application is in a suitable format.1603 Listings of individual cases from EudraVigilance database may be retrieved to support the PSUR1604 assessment.1605 Further to the above verifications, the Agency acknowledges receipt of the report and starts the1606 procedure in accordance with the official starting dates published on the Agency's website. The1607 submission deadlines and detailed procedural timetables are published as a generic calendar on the1608 Agency's website.1609 The published timetables identify the submission, start and finish dates of the procedures as well as1610 other interim dates/milestones that occur during the procedure.1611 During the assessment, additional listings of individual cases may be requested by the PRAC1612 Rapporteur through the Agency, for adverse reactions of special interest and should be provided by the1613 marketing authorisation holder(s) within an established timeframe to be included in the request. This1614 may be accompanied by a request for an analysis of cases classified as non-serious.1615 During the drafting of the assessment report, the PRAC Rapporteur shall closely collaborate with the1616 CHMP Rapporteur [REG Art 28(3)].1617 The PRAC Rapporteur shall prepare an assessment report and send it to the Agency and to the1618 members of the PRAC [REG Art 28(3)] within 60 days of the start of the procedure.1619 The Agency shall send the PRAC Rapporteur’s preliminary assessment report to the marketing1620 authorisation holder [REG Art 28(3)].1621 By Day 90, the marketing authorisation holder and members of the PRAC may send comments on the1622 PRAC Rapporteur’s preliminary assessment report to the Agency and the PRAC Rapporteur. Those1623 comments should also include responses to outstanding issues or questions raised by the PRAC1624 Rapporteur in the preliminary assessment report and which can be addressed within the timeframe of1625 the comments phase.1626 Following receipt of comments, the PRAC Rapporteur shall prepare an updated assessment report [REG1627 Art 28(3)] within 15 days (i.e. by Day 105). The updated assessment report is made available to the1628 members of the PRAC.1629 An oral explanation to the PRAC can be held at the request of the PRAC or the marketing authorisation1630 holder in case of recommendation for a revocation or suspension of the marketing authorisation, a new1631 contraindication, a restriction of the indication or a reduction of the recommended dose.1632 The PRAC shall adopt the updated assessment report with or without further changes at its next1633 meeting [REG Art 28(3)], together with a recommendation on the maintenance of the marketing1634 authorisation or the need to vary, suspend or revoke the marketing authorisation. The PRAC1635 recommendation may also highlight the need to conduct a post-authorisation safety study, request an1636 update of the RMP, review of safety issues and/or close monitoring of events of interest.1637 Divergent positions of PRAC members and the grounds on which they are based shall be reflected in1638 the recommendation issued by the PRAC [REG Art 28(3)].1639 The Agency shall include the PRAC recommendation and adopted assessment report in the repository,1640 and forward both to the marketing authorisation holder [REG Art 28(3)].1641
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 51/69 Further to adoption at the PRAC meeting, in case of any regulatory action is recommended, the1642 assessment report and PRAC recommendation are sent to the CHMP for adoption of an opinion for the1643 centrally authorised product concerned as described in VII.C.4.2.3..1644 VII.C.4.2.2. Assessment of PSURs for medicinal products subject to different marketing1645 authorisations containing the same active substance (EU single assessment)1646 This section describes the assessment of PSURs for medicinal products subject to different marketing1647 authorisations containing the same active substance or the same combination of active substances1648 whether or not held by the same marketing authorisation holder and for which the frequency and dates1649 of submission of PSUR have been harmonised in the list of EU reference dates. This could include a1650 mixture of centrally authorised products, products authorised through the mutual recognition and1651 decentralised procedures and purely nationally authorised products [DIR Art 107e to 107g] (so-called1652 PSUR “EU single assessment” procedure).1653
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 52/69 Figure VII.7. PSUR assessment procedure for “EU single assessment”1654 Receipt of PSUR(s) from MAH(s) Technical validation by the Agency Start Rapporteur/MS preliminary assessment report 60 days Comments from MAH(s) and NCAs 30 days Rapporteur/MS updated assessment report 15 days PRAC recommendation At the next PRAC meeting Is variation, suspension or revocation of the marketing authorisation is recommended PRAC recommendation sent to MAH(s) No CAP included? Yes PRAC recommendation received by CMDh No CMDh position with timetable for implementation Majority position sent to EC, MAH(s) and NCAs Agreed position sent to MAH(s) and NCAs Implementation at national level according to the appropriate procedure EC decision to NCAs on measures to be taken Implementation at national level according to the appropriate procedure PRAC recommendation received by CHMP CHMP opinion with timetable for implementation 30 days Opinion sent to EC, MAH(s) and NCA EC decision to update centralised MA EC decision to NCAs on measures to be taken Implementation at national level according to the appropriate procedure 30 days By majorityBy consensus Yes For CAPs For Non-Caps 1655
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 53/69 The assessment of PSURs for medicinal products, also called “EU single assessment”, shall be1656 conducted by [DIR Art 107e(1)]:1657  a “Member State” appointed by the CMDh where none of the marketing authorisations concerned1658 has been granted in accordance with the centralised procedure;1659  a “Rapporteur” appointed by the PRAC, where at least one of the marketing authorisations1660 concerned has been granted in accordance with the centralised procedure (hereinafter referred to1661 as “PRAC Rapporteur”).1662 The PSUR EU single assessment procedure is coordinated by the Agency. Upon receipt, the Agency1663 should perform a technical validation of the reports to ensure that the PSURs applications are in a1664 suitable format.1665 Upon establishment of the list of all medicinal products for human use authorised in the EU referred to1666 in REG Art 57, the Agency should ensure that all marketing authorisation holder(s) of the given1667 substance have submitted PSUR(s), as required. In the event where a PSUR has not been submitted,1668 the Agency should contact the concerned marketing authorisation holder(s). However, this will not1669 preclude the start of the single assessment procedure for other PSUR(s) of the same active substance.1670 Listings of individual cases from EudraVigilance database may be retrieved to support the PSURs1671 assessment.1672 Further to the above verifications, the Agency acknowledges receipt of the report(s) and starts the1673 procedure in accordance with the official starting dates published on the Agency's website. The1674 submission deadlines and full procedural detailed timetables are published as a generic calendar on the1675 Agency's website.1676 The published timetables identify the submission, start and finish dates of the procedures as well as1677 other interim dates/milestones that occur during the procedure.1678 Further to the start of procedure, the PRAC Rapporteur or Member State conducts the single1679 assessment of all PSURs submitted for the given active substance.1680 During the assessment, additional listings of individual cases may be requested by the PRAC1681 Rapporteur or Member State through the Agency for adverse drug reactions of special interest and1682 should be provided by the marketing authorisation holder(s) within an established timeframe to be1683 included in the request. This may be accompanied by a request for an analysis of cases classified as1684 non-serious.1685 The PRAC Rapporteur or Member State shall prepare an assessment report and send it to the Agency1686 and to the Member States concerned [DIR Art 107e(2)] within 60 days of the start of the procedure.1687 This preliminary assessment report should be circulated to the members of the PRAC.1688 The Agency shall send the PRAC Rapporteur’s/Member State preliminary assessment report to the1689 concerned marketing authorisation holder(s) [DIR Art 107e(2)].1690 By Day 90, the marketing authorisation holder(s), Member States and members of the PRAC as1691 applicable may send comments on the PRAC Rapporteur’s/Member State’s preliminary assessment1692 report to the Agency and the PRAC Rapporteur/Member State, as applicable. Those comments should1693 also include responses to outstanding issues or questions raised by the PRAC Rapporteur/Member1694 State in the preliminary assessment report and which can be addressed within the timeframe of the1695 comments phase.1696 1697
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 54/69 Following receipt of comments, the PRAC Rapporteur/Member State shall prepare an updated1698 assessment report [DIR Art 107e (3)] within 15 days (i.e. by Day 105). The updated assessment1699 report is forwarded to the members of the PRAC.1700 An oral explanation to the PRAC can be held at the request of the PRAC or the marketing authorisation1701 holder in case of recommendation for a revocation or suspension of the marketing authorisation, a new1702 contraindication, a restriction of the indication or a reduction of the recommended dose.1703 The PRAC shall adopt the updated assessment report with or without further changes at its next1704 meeting [DIR Art 107e(3)], together with a recommendation on maintenance of the marketing1705 authorisation or the need to vary, suspend or revoke the marketing authorisation. The PRAC1706 recommendation may also highlight the need to conduct a post-authorisation safety study (see Module1707 VIII), request an update of the RMP (see Module V), review of safety issue and/or close monitoring of1708 events of interest.1709 Divergent positions of PRAC members and the grounds on which they are based shall be reflected in1710 the recommendation issued by the PRAC [DIR Art 107e(3)].1711 The Agency shall include the PRAC recommendation and adopted assessment report in the repository,1712 and forward both to the marketing authorisation holder(s) [DIR Art 107e(3)].1713 Further to adoption at the PRAC meeting, in case of any regulatory action is recommended, the1714 assessment report and PRAC recommendation are sent to:1715  the CHMP where at least one centrally authorised product is included in the single assessment, for1716 adoption of an opinion as described in VII.C.4.2.3.;1717  the CMDh where no centrally authorised product is included in the single assessment, for1718 agreement of a position as described in VII.C.4.2.4..1719 VII.C.4.2.3. Single assessment including at least one centrally authorised product leading to1720 a CHMP opinion1721 The CHMP acknowledges receipt of the PRAC recommendation and assessment report, in case of any1722 regulatory action, at their next meeting following the PRAC adoption. Within 30 days from receipt, the1723 CHMP shall consider the PRAC assessment report and recommendation and adopt an opinion on the1724 maintenance, variation, suspension, revocation of the marketing authorisation(s) concerned [DIR1725 107g(3)].1726 An oral explanation to the CHMP can be held at the request of the CHMP or the marketing authorisation1727 holder(s) only in case of differences with the PRAC recommendation where CHMP considers the1728 possibility of adopting an opinion on the suspension or revocation of the marketing authorisation(s), a1729 new contraindication, a restriction of the indication or a reduction of the recommended dose.1730 The opinion will contain the following:1731  the final assessment report and recommendation adopted by the PRAC;1732  detailed explanation of the scientific grounds for differences with the PRAC recommendation, if1733 applicable [DIR Art 107g(3)];1734  in the case of a CHMP opinion to vary the marketing authorisation(s):1735  the scientific conclusions and grounds recommending the variation to the terms of the1736 marketing authorisation;1737
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 55/69  for centrally authorised products, revised product information and if applicable, conditions1738 imposed to the marketing authorisation holder and where appropriate, the conditions or1739 restrictions imposed to the Member States for the safe and effective used of the medicinal1740 product, in accordance with the provision provided in DIR Art 127a;1741  for nationally authorised products, including those authorised through the mutual recognition1742 and decentralised procedures, an annex indicating the new safety warnings and key risk1743 minimisation recommendations to be included in the relevant sections of the product1744 information as applicable.1745  in the case of a CHMP opinion to suspend the marketing authorisation(s), the scientific conclusions1746 together with the grounds for suspension and conditions for lifting the suspension;1747  in the case of a CHMP opinion to revoke the marketing authorisation(s), the scientific conclusions1748 together with the grounds for revocation;1749  divergent positions of CHMP members, where applicable.1750 Further to adoption, the Agency should send the CHMP opinion together with its annexes and1751 appendices to the European Commission, marketing authorisation holder(s) and competent authorities1752 in Member States.1753 The final assessment conclusions and recommendations are published in the European medicines web-1754 portal (VII.C.7.).1755 a. Post CHMP opinion - Centrally authorised products1756 Where the CHMP opinion states that the terms of the marketing authorisation(s) needs to be varied,1757 the marketing authorisation holder(s) of centrally authorised products should provide the translations1758 of the product information in all EU official languages, in accordance with the translation timetable1759 adopted by the CHMP.1760 Further to receipt of a CHMP opinion stating that regulatory action to the concerned marketing1761 authorisation is necessary, the European Commission shall adopt a decision addressed to marketing1762 authorisation holders to vary, suspend or revoke the marketing authorisation(s) of centrally authorised1763 product(s) [DIR Art 107g(4b)].1764 Further to adoption, the European Commission should notify the decisions amending the terms of the1765 marketing authorisation of centrally authorised products to the marketing authorisation holder(s).1766 b. Post CHMP opinion - Nationally authorised products, including those authorised through1767 the mutual recognition and decentralised procedures1768 Further to receipt of a CHMP opinion stating that regulatory action to the concerned marketing1769 authorisations is necessary, the European Commission shall adopt a decision addressed to the1770 competent authorities in Member States concerning the measures to be taken [DIR Art 107g(a)] in1771 respect of nationally authorised products, including those authorised through the mutual recognition1772 and decentralised procedures.1773 Further to the receipt of the decision from the European Commission, the competent authorities in1774 Member States shall take the necessary measures to vary, suspend or revoke the marketing1775 authorisation(s) within 30 days [DIR Art 107g(4)].1776
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 56/69 VII.C.4.2.4. Single assessment not including centrally authorised product leading to a CMDh1777 position1778 The CMDh acknowledges receipt of the PRAC recommendation and assessment report, in case of any1779 regulatory action, at their next meeting following the PRAC adoption.1780 Within 30 days from receipt, the CMDh shall consider the PRAC assessment report and1781 recommendation and reach a position on the maintenance, variation, suspension, revocation of the1782 marketing authorisation(s) concerned [DIR Art 107g(1)].1783 An oral explanation to the CMDh can be held at the request of the CMDh or the marketing1784 authorisation holder(s), only in case of differences with the PRAC recommendation where the CMDh1785 considers the possibility to reach a position on the suspension or revocation of the marketing1786 authorisation(s), a new contraindication, a restriction of the indication or a reduction of the1787 recommended dose.1788 The position will contain the following:1789  the final assessment report and recommendation adopted by the PRAC;1790  detailed explanation of the scientific grounds for differences with the PRAC recommendation, if1791 applicable [DIR Art 107g(2)];1792  in the case of a CMDh position to vary the marketing authorisation(s), the scientific conclusions1793 and grounds recommending the variation to the terms of the marketing authorisation and an1794 annex indicating the new safety warnings and key risk minimisation recommendations to be1795 included in the relevant sections of the product information, as applicable;1796  in the case of a CMDh position to suspend the marketing authorisation(s), the scientific conclusions1797 together with the grounds for suspension and conditions for lifting the suspension;1798  in the case of a CMDh position to revoke the marketing authorisation(s), the scientific conclusions1799 together with the grounds for revocation;1800  divergent position(s) for the CMDh members, where applicable.1801 The final assessment conclusions and recommendations shall be published by the Agency in the1802 European medicines web-portal [DIR Art 107l] (VII.C.7.).1803 If the CMDh position is reached by consensus:1804 The position agreed including the action to be taken is recorded by the chairperson in the minutes of1805 the CMDh meeting where agreed.1806 The chairman shall send the agreed CMDh position [DIR Art 107g(2)] and its appendices to the1807 marketing authorisation holder(s) and competent authorities in Member States.1808 Further to receipt of the CMDh position stating that regulatory action to the concerned marketing1809 authorisation is necessary, the competent authorities in Member States shall adopt necessary1810 measures to vary, suspend or revoke the marketing authorisation(s) concerned in accordance with the1811 timetable for implementation determined in the agreed position [DIR Art 107g(2)].1812 In case the position of the CMDh agreed that variation to the terms of marketing authorisation is1813 required, the marketing authorisation holder(s) shall submit the relevant variation to that effect within1814 the timetable for implementation [DIR Art 107g(2)] as appended to the agreed position.1815 If the CMDh position is reached by majority vote:1816
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 57/69 The majority position on the action to be taken is recorded by the chairman in the minutes of the1817 CMDh meeting where agreed.1818 The majority position of the CMDh together with its annexes and its appendices, including translations1819 in all EU official languages where applicable, shall be forwarded to the European Commission [DIR Art1820 107g(2)]. The position of the CMDh should also be forwarded to the competent authorities in Member1821 States.1822 Further to receipt of a CMDh position stating that regulatory action to the concerned marketing1823 authorisation is necessary, the European Commission shall adopt decision(s) [DIR Art 107g(2)]1824 addressed to the competent authorities in Member States in order for them to vary, suspend or revoke1825 the marketing authorisation(s) of nationally authorised product(s) which is addressed to marketing1826 authorisation holders.1827 Further to receipt of the decision from the European Commission, the competent authorities in Member1828 States shall take the necessary measures to maintain, vary, suspend or revoke the marketing1829 authorisation(s) within 30 days [DIR Art 107g(2)].1830 VII.C.4.3. Relationship between PSUR and risk management plan1831 The general relationship between the risk management plan (RMP) and the PSUR is described in1832 Module V, while an overview of the common RMP/PSUR modules is provided in VII.C.4.3.1..1833 During the preparation of a PSUR, the marketing authorisation holder should consider whether any1834 identified or potential risks discussed within the PSUR is important and requires an update of the RMP.1835 In these circumstances, updated revised RMP including the new important safety concern should be1836 submitted with the PSUR and assessed in parallel, following the timetable for the assessment of PSUR1837 as described above.1838 If important safety concerns are identified by the national competent authorities in the Member States1839 during the assessment of a PSUR and no updated RMP or no RMP has been submitted,1840 recommendations should be made to submit an update or a new RMP within a defined timeline.1841 VII.C.4.3.1. PSUR and risk management plan – common modules1842 The proposed modular formats for the PSUR and the RMP aim to address duplication and facilitate1843 flexibility by enabling common PSUR/RMP sections to be utilised interchangeably across both reports.1844 Common sections with the above mentioned reports are identified in Table VII.1.:1845 Table VII.1. Common sections between PSUR and RMP1846 PSUR section RMP section Section 3 – “Actions taken in the reporting interval for safety reasons” Part II, module SV – “Post-authorisation experience”, section “Regulatory and marketing authorisation holder action for safety reason” Sub-section 5.2 – “Cumulative and interval patient exposure from marketing experience” Part II, module SV – “Post-authorisation experience”, section “Non-study post- authorisation exposure” Sub-section 16.1 – “Summary of safety concerns” Part II, module SVIII – “Summary of the safety concerns” (as included in the version of the RMP which was current at the beginning of the PSUR reporting interval) Sub-section 16.4 – “Characterisation of risks” Part II, Module SVII – “Identified and potential
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 58/69 PSUR section RMP section risks” Sub-section 16.5 – “Effectiveness of risk minimisation (if applicable)” Part V – “Risk minimisation measures”, section “Evaluation of the effectiveness of risk minimisation activities” VII.C.5. EU-specific requirements for periodic safety update reports1847 The scientific evaluation of the risk-benefit balance of the medicinal product included in the PSUR1848 detailed in VII.B.5. shall be based on all available data, including data from clinical trials in1849 unauthorised indications and populations according to the provisions of DIR Art 107b and IR Art 34(1).1850 The EU-specific requirements should be included in the PSUR EU regional appendix.1851 VII.C.5.1. PSUR EU regional appendix, sub-section “Proposed product1852 information”1853 The assessment of the need for amendments to the product information is incorporated within the1854 PSUR assessment procedure in the EU. The regulatory opinion/position should include1855 recommendations for updates to product information where needed. Marketing authorisation holders1856 should provide the necessary supportive documentation and references within the PSUR to facilitate1857 this.1858 Within the PSUR, the marketing authorisation holder is required to consider the impact of the data and1859 evaluations presented within the report, on the marketing authorisation. Based on the evaluation of1860 the cumulative safety data and the risk-benefit analysis, the marketing authorisation holder shall draw1861 conclusions in the PSUR as to the need for changes and/or actions, including implications for the1862 approved SmPC(s) for the product(s) for which the PSUR is submitted [IR Art 34 (5)].1863 In this sub-section, the marketing authorisation holder should provide the proposals for product1864 information (SmPC and package leaflet) based on the above mentioned evaluation. These should be1865 based on all EU authorised indications.1866 A track change version of the proposed SmPCs and package leaflets based on the assessment and1867 conclusions of the PSUR should be provided. For centrally authorised medicinal products, the proposed1868 product information should also be submitted to Module 1.3.1 of the Electronic Common Technical1869 Document (eCTD).1870 All the SmPCs and packages leaflets covered by the PSUR should be reviewed to ensure that they1871 reflect the appropriate information accordingly to the cumulative data included and analysed in the1872 PSUR.1873 Amendments to the product information should not be postponed or delayed until the PSUR submission1874 and amendments not related to the information presented in the PSUR, should not be proposed within1875 the PSUR procedure. It is the obligation of the marketing authorisation holder to submit a variation in1876 accordance with the Regulation (EC) No 1234/2008 on variations to the terms of a marketing1877 authorisation.1878 VII.C.5.2. PSUR EU regional appendix, sub-section “reference information comparison”1879 In this sub-section, the marketing authorisation holder should highlight any important differences1880 between the reference information in use and the proposals for product information in the EU.1881 Examples of important differences may be those relating to adverse drug reactions, contraindications,1882
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 59/69 warnings, interactions and overdose. For the purposes of this comparison, the reference information in1883 effect at the end of the reporting interval may be used but the marketing authorisation holder should1884 highlight any important changes proposed/introduced in the time period between the data lock point1885 and submission of the PSUR.1886 VII.C.5.2. PSUR EU regional appendix, sub-section “Proposed additional1887 pharmacovigilance and risk minimisation activities”1888 Considering the provision established in IR Art 34 (5), this sub-section should include proposals for1889 additional pharmacovigilance and additional risk minimisation activities based on the conclusions and1890 actions of the PSUR, including a statement of the intention to submit a RMP or an updated RMP when1891 applicable.1892 VII.C.5.3. PSUR EU regional appendix, sub-section “Summary of ongoing1893 safety concerns”1894 In order to support the information provided in the PSUR section 16.1 “Summary of safety concerns”1895 (see VII.B.5.16.1.), Table 1.10 (according to the current RMP template) “Summary – Ongoing safety1896 concerns” should be included in this PSUR sub-section. This table should be extracted from the version1897 of RMP available at the beginning of the PSUR reporting interval (see Module V).1898 VII.C.5.4. PSUR EU regional appendix, sub-section “Reporting of results1899 from post-authorisation safety studies”1900 Findings from both interventional and non-interventional (for further guidance see Module VIII) post-1901 authorisation safety studies (PASS) should be reported in the PSUR. While the marketing authorisation1902 holder should inform competent authorities in Member States and the Agency as applicable about any1903 new information that may impact on the risk-benefit balance immediately, the PSUR should provide1904 comprehensive information on the findings of all PASS, both interventional and non-interventional, in1905 PSUR sections 7 and 8 respectively.1906 Final study reports for studies conducted with the primary aim of identifying, characterising or1907 quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the1908 effectiveness of risk management measures which were completed during the reporting interval should1909 also be included as an annex to the PSUR. For such studies discontinued during the reporting interval,1910 the reasons for stopping the study should also be explained.1911 If an important safety concern has been identified in the course of a study, regardless of whether it1912 has been detected through pre-specified methods and whether the study is considered a PASS, the1913 marketing authorisation holder and specifically the qualified person responsible for pharmacovigilance1914 (QPPV) will have informed the relevant competent authorities in Member States immediately.1915 PSURs should not be used as the initial communication method either for the submission of final study1916 reports to the competent authorities in Member States or for the notification of any new information1917 that might influence the evaluation of the risk-benefit balance.1918 VII.C.5.5. PSUR EU regional appendix, sub-section “Effectiveness of risk1919 minimisation”1920 Risk minimisation activities are public health interventions intended to prevent the occurrence of an1921 adverse drug reaction(s) associated with the exposure to a medicinal product or to reduce its severity1922 should it occur. The success of risk minimisation activities in delivering these objectives needs to be1923
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 60/69 evaluated throughout the lifecycle of a product to ensure that the burden of adverse reactions is1924 minimised and hence the overall risk-benefit balance is optimised. In accordance with section1925 VII.B.5.16.5., evaluation of broad global experience should be reflected in the body of the report.1926 This sub-section should additionally provide an evaluation of the effectiveness of routine and/or1927 additional risk minimisation activities specifically relevant to an EU context. This should take account of1928 regulatory imposed obligations for implementation of risk minimisation measures in addition to the1929 overall requirement for monitoring of safety and benefit-risk. Results of any studies to assess the1930 impact or other formal assessment(s) of risk minimisation activities in the EU should be included when1931 available. As part of this critical evaluation, the marketing authorisation holder should make1932 observations on factors contributing to the success or weakness of risk minimisation activities. If a1933 particular risk minimisation strategy proves ineffective, then alternative activities need to be put in1934 place. In certain cases, it may be judged that risk minimisation cannot control the risks to the extent1935 possible to ensure a positive risk-benefit balance and that the medicinal product needs to be withdrawn1936 either from the market or restricted to those patients in whom the benefits outweigh the risks. More1937 extensive guidance on monitoring the effectiveness of risk minimisation activities is included in Module1938 XVI. As a principle, the marketing authorisation holder should distinguish in their evaluation between1939 implementation success and attainment of the intended outcome.1940 VII.C.6. Quality systems and record management systems for PSURs in the1941 EU network1942 VII.C.6.1. Quality systems and record management systems at the level of1943 the marketing authorisation holder1944 Specific quality system procedures and processes shall be in place in order to ensure the update of1945 product information by the marketing authorisation holder in the light of scientific knowledge, including1946 the assessments and recommendations made public via the European medicines web-portal, and on1947 the basis of a continuous monitoring by the marketing authorisation holder of information published on1948 the European medicines web-portal [IR Art 11(1)(f)].1949 It is the responsibility of the marketing authorisation holder to check regularly the list of EU reference1950 dates and frequency of submission published in the European medicines web-portal to ensure1951 compliance with the PSUR reporting requirements for their medicinal products (see VII.C.3.).1952 Systems should be in place to schedule the production of PSURs according to:1953  the list of EU reference dates and frequency of PSURs submission; or1954  the conditions laid down in the marketing authorisation; or1955  the standard PSUR submission schedule established according to DIR Art 107c(2) for products1956 authorised before 2 July 2012 (for centrally authorised products) and 21 July 2012 (for nationally1957 authorised products) as applicable (without any conditions in their marketing authorisation or not1958 included in the list of EU references dates and frequency of submission or not affected by the1959 derogation established in [DIR Art 107b(3)]); or1960  ad hoc requests for PSURs by a competent authority in a Member State or the Agency.1961 For those medicinal products where the submission of an RMP is not required, the marketing1962 authorisation holder should maintain on file a specification of important identified risks, important1963 potential risks and important missing information in order to support the preparation of the PSURs.1964
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 61/69 The marketing authorisation holder should have procedures in place to follow the requirements1965 established by the Agency for the submission of PSURs.1966 The QPPV shall be responsible for the establishment and maintenance of the pharmacovigilance system1967 [DIR Art 104(e)] and therefore should ensure that the pharmacovigilance system in place enables the1968 compliance with the requirements established for the production and submission of PSURs. In relation1969 to the medicinal products covered by the pharmacovigilance system, specific additional responsibilities1970 of the QPPV in relation to PSURs should include:1971  ensuring the necessary quality, including the correctness and completeness, of the data submitted1972 in the PSURs;1973  ensuring full response according to the timelines and within the procedure agreed (e.g. next PSUR)1974 to any request from the competent authorities in Member States and the Agency related to PSURs;1975  awareness of the PSUR and assessment report conclusions, PRAC recommendations, CHMP1976 opinions, CMDh positions and European Commission decisions in order to ensure that appropriate1977 action takes place.1978 The record retention times for product-related documents in Module I also apply to PSURs and source1979 documents related to the creation of PSURs, including documents related to actions taken for safety1980 reasons, clinical trials and post-authorisation studies, relevant benefit information and documents1981 utilised for the calculation of patient exposure.1982 VII.C.6.2. Quality systems and record management systems at the level of1983 the European Medicines Agency1984 The application of the Agency’s quality system (see Module I) should support compliance by the1985 Agency when fulfilling its tasks and responsibilities for the management of PSUR procedures and EU1986 single assessments.1987 The Agency should have in place a process to technically validate the completeness of PSUR1988 submissions.1989 Line listings and summary tabulations from the EudraVigilance database utilised to support the PSUR1990 assessment should be created using reports by means of the EudraVigilance data analysis system.1991 Effective communication and circulation of PSURs and related documents is crucial for the successful1992 completeness of the procedure; therefore processes have to be in place for the circulation of1993 documents between the Agency, marketing authorisation holders, the Commission and the competent1994 authorities in Member States. Where applicable, the procedures should establish the necessity for1995 quality checks with the aim to remove any information of a personal or commercially confidential1996 nature.1997 Written procedures should reflect the different steps to follow for the maintenance of the list of EU1998 references dates and frequency of submission of PSURs published by the Agency in the European1999 medicines web-portal (see VII.C.3.).2000 Prior to the publication of summaries of PSUR assessment reports in the European medicines web-2001 portal (see VII.C.7.) the appropriate personnel at the Agency should adhere to the procedures2002 established for web publication of documents produced by the Agency or competent authorities in the2003 Member States.2004 All records related to PSURs created by the Agency’s staff members, experts or consultants are the2005 property of the Agency and all PSURs and related documents received are in the custody of the2006
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 62/69 Agency. Both types of PSURs records (created or received by the Agency) are subject to the Agency’s2007 overall control via the PSUR repository set up according to the provisions laid down in REG Art 25a.2008 The Agency’s policy on records management (EMEA/590678/2007)22 , provides the basis for a2009 consistent, sustainable and efficient records management program and it has been developed in2010 accordance with the commonly recognised international standard for records management, “ISO2011 15489-1:2001 Information and documentation – Records management23 ”. According to the records2012 classification stated by the Agency’s policy, PSURs would be considered business, legal, evidential and2013 research/historical value records.2014 The record retention times for product-related documents in Module I also apply to PSUR- system2015 related documents (e.g. standard operating procedures) and PSUR -related documents (e.g. PSURs,2016 assessment reports, the data retrieved from the EudraVigilance database or other data used to support2017 the PSUR assessment).2018 VII.C.6.3. Quality systems and record management systems at the level of2019 the competent authorities in Member States2020 Each competent authority in the Member States shall have in place a pharmacovigilance system [DIR2021 Art 101] for the surveillance of medicinal products and for receipt and evaluation of all2022 pharmacovigilance data including PSURs. For the purpose of operating its tasks relating to PSURs in2023 addition to the pharmacovigilance system the national competent authorities in Member States should2024 implement a quality system (see Module I).2025 Competent authorities in the Member States should monitor marketing authorisation holders for2026 compliance with regulatory obligations for PSURs. Additionally, competent authorities should exchange2027 information in cases of non-compliance and take appropriate regulatory actions as required.2028 No PSUR assessment at EU level is foreseen for purely nationally authorised products authorised in2029 only one Member State; therefore the national competent authority in the Member State where the2030 medicinal product is authorised should have procedures in place for the assessment of PSURs related2031 to those medicinal products.2032 The procedures established by the national competent authorities in Member States for the2033 performance of the EU single assessment of PSURs, should be in line with the procedures established2034 by the Agency for the coordination of PSUR assessment in the EU regulatory network (see VII.C.4.).2035 These procedures should establish effective communication across the EU regulatory network and the2036 actions to be taken regarding the variation, suspension or revocation of the marketing authorisation2037 following the PRAC recommendations, CHMP opinion, CMDh position and European Commission2038 decision as applicable.2039 The procedures established by the Agency for the use of the PSUR repository to support the single2040 assessment, should be followed by the national competent authorities in Member States.2041 Where tasks related to PSUR procedures are delegated to third parties, the national competent2042 authorities in Member States should ensure that they are subject to a quality system in compliance2043 with the obligations provided by the European legislation.2044 The record retention times for product-related documents in Module I also apply to PSUR- system2045 related documents (e.g. standard operating procedures) and PSUR -related documents (e.g. PSURs,2046 assessment reports, the data retrieved from the EudraVigilance database or other data used to support2047 the PSUR assessment).2048 22 www.ema.europa.eu 23 www.ISO.org
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 63/69 VII.C.7. Transparency2049 VII.C.7.1. Publication of PSUR-related documents on the European2050 medicines and national medicines web-portals2051 The following documents shall be made publicly available by means of the European medicines web-2052 portal [DIR Art 107l, REG Art 26(g)]:2053  list of EU reference dates and frequency of submission of PSURs (see VII C.3.);2054  final assessment conclusions of the adopted assessment reports;2055  PRAC recommendations including relevant annexes;2056  CMDh position including relevant annexes and where applicable, detailed explanation on scientific2057 grounds for any differences with the PRAC recommendations;2058  CHMP opinion including relevant annexes and where applicable, detailed explanation on scientific2059 grounds for any differences with the PRAC recommendations;2060  European Commission decision.2061 The version and date of publication are reflected in each document as they define the issue of the2062 PRAC recommendations, CHMP opinions, CMDh positions and European Commission decisions at a2063 certain point of time.2064 Links between the European medicines web-portal and the National medicines web-portals should be2065 made whenever possible and relevant.2066 Any personal or confidential data made public by the Agency or the competent authorities in Member2067 States as referred to in paragraphs 2 and 3 of Article 106a of Directive 2001/83/EC shall be deleted2068 unless considered necessary in terms of protection of the public health [DIR Art 106a(4)].2069 VII.C.8. Renewal of marketing authorisations2070 Marketing authorisations need to be renewed after 5 years on the basis of a re-evaluation of the risk-2071 benefit balance in order to continue to be valid to place the product on the market. This renewal is2072 irrespective of whether the marketing authorisation is suspended. Further details on the procedure and2073 the documentation requirements can be found in the current versions of the “Guideline on Processing2074 of Renewals in the Centralised Procedure” (EMEA/CHMP/2990/00) for Centralised products and the2075 “CMDh Best Practice Guide on the processing of renewals in the MRP/DCP” (CMDh/004/2005) for other2076 products.2077 No PSURs, addendum reports and summary bridging reports should be submitted within the renewal2078 application. The clinical overview should include an addendum containing the relevant sections for the2079 re-assessment of the risk-benefit balance of the medicinal product. These sections are identified in the2080 above-mentioned guidelines for renewal. Marketing authorisation holders are advised to consider this2081 GVP Module VII as guidance for the preparation of the addendum to the clinical overview.2082 Following the submission of a renewal application, the PRAC may be consulted for medicinal products2083 authorised through the centralised procedure as regards safety issues. For nationally authorised2084 products, including those authorised through the mutual recognition or decentralised procedure, the2085 PRAC may also be consulted upon request by a competent authority in a Member State on the basis of2086 safety concerns.2087
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 64/69 Conditional marketing authorisations should be renewed annually [REG Art 14(7)]. Further details on2088 the procedure and the documentation to be submitted can be found in the “Guideline on the scientific2089 application and the practical arrangements necessary to implement Commission Regulation (EC) No2090 507/2006 on the conditional marketing authorisation for medicinal products for human use falling2091 within the scope of regulation (EC) no 726/2004” ( EMEA/509951/2006).2092 VII.C.9. Transition and interim arrangements2093 VII.C.9.1. Submission and availability of documents before the Agency’s2094 repository is in place2095 The Agency shall, in collaboration with the competent authorities in Member States and the European2096 Commission set up and maintain a repository for PSURs and the corresponding assessment reports so2097 that they are fully and permanently accessible to European Commission, the competent authorities in2098 Member States, the PRAC, the CHMP and the CMDh [REG Art 25a].2099 The repository shall undergo an independent audit before the functionalities are announced by the2100 Agency’s management board [REG Art 25a].2101 As established in the transitional provisions introduced in Directive 2010/84/EU Art 2(7), until the2102 Agency can ensure the functionalities agreed for the repository, marketing authorisation holders under2103 the obligation to submit PSURs irrespective of whether the medicinal product is authorised in one or2104 more Member States and irrespective of whether the active substance or combination of active2105 substances is on the EU reference date list shall submit the PSURs to all competent authorities in2106 Member States in which the medicinal products are authorised. For the substances or combination of2107 active substances subject to a single assessment or for which an EU reference date has been2108 established, the PSURs should be also sent to the Agency.2109 The competent authorities in Member States requirements for the submission of PSURs during this2110 transitional period are published in the Agency web-site24 .2111 From 12 months after the functionalities of the repository have been established and have been2112 announced by the Agency, the marketing authorisation holders shall submit the PSURs electronically to2113 the Agency regardless of the authorisation procedure of the medicinal product [DIR Art 107b(1)]. The2114 competent authorities in Member States shall ensure that this obligation applies as required [DIR Art2115 2(7)].2116 Once the structured electronic format “ePSUR”, based on content agreed in the ICH-E2C(R2), becomes2117 available, marketing authorisation holders will have the possibility to submit PSURs and related2118 documents automatically via an electronic gateway.2119 Until the repository is in place, the following documents should be circulated through a dedicated2120 mailbox or according to the instructions for submissions published by the Agency:2121  preliminary assessment report created by the PRAC Rapporteur/Member State within 60 days of2122 the start of the procedure. The report should be circulated to the Agency and the members of the2123 PRAC. The Agency should send the report to the concerned marketing authorisation holder(s);2124  comments submitted by the marketing authorisation holders(s) and members of the PRAC by Day2125 90 on the PRAC Rapporteur/Member State preliminary assessment report. These comments should2126 also be circulated to all members of the PRAC by the marketing authorisation holder.2127 24 www.ema.europa.eu
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 65/69  updated PRAC Rapporteur/Member State assessment report created within 15 days (i.e. by Day2128 105) should be forwarded to the Agency and members of the PRAC.2129 Further to adoption, the Agency should send the CHMP opinion together with its annexes and2130 appendices to the European Commission, marketing authorisation holder(s) and competent authorities2131 in Member States, through secure email until the repository is in place.2132 VII.C.9.2. Quality systems and record management systems at the level of2133 the competent authorities in Member States2134 Special considerations should be taken for the management of the PSURs submitted to the concerned2135 competent authorities in Member States until the Agency can ensure the functionalities agreed for the2136 PSUR repository and 12 months after the establishment of the repository according to the transitional2137 provisions.2138 VII.C.9.3. Publication of the EU list of union references dates and start of2139 the EU-PSUR single assessment procedure2140 As stated in VII.C.3.6., the list of EU reference dates and frequency of submission should be published2141 in the European medicines web-portal, nevertheless, the EU single assessment procedure for2142 substances included only in nationally authorised products, detailed in VII.C.4.2.2., and VII.C.4.2.4.2143 will be delayed until funds are available.2144 2145 2146
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 66/69 VII.APPENDICES2147 VII.Appendix 1. Examples of tabulations for estimated exposure and2148 adverse events/reactions data2149 Marketing authorisation holders can modify these examples tabulations to suit specific situations, as2150 appropriate.2151 Table VII.2. Estimated cumulative subject exposure from clinical trials2152 Estimates of cumulative subject exposure, based upon actual exposure data from completed clinical2153 trials and the enrolment/randomisation schemes for ongoing trials.2154 Treatment Number of Subjects Medicinal product Comparator Placebo 2155 Table VII.3. Cumulative subject exposure to investigational drug from completed clinical trials by age2156 and sex2157 Number of subjects Age range Male Female Total Data from completed trials as of [date]2158 Table VII.4. Cumulative subject exposure to investigational drug from completed clinical trials by2159 racial/ethnic group2160 Racial/ethnic group Number of subjects Asian Black Caucasian Other Unknown Total Data from completed trials as of [date]2161 Table VII.5. Cumulative exposure from marketing experience2162 Indication Sex Age (years) Dose Formulation Region Male Female 2to≤16 >16to65 >65 Unknown <40 ≥40 Unknown Intravenous Oral EU Japan Colombia US/Canada Other Overall Depression Migraine
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 67/69 Table VII.5 includes cumulative data obtained from day/month/year throughout day/month/year, where available2163 Table VII.6. Interval exposure from marketing experience2164 Indication Sex Age (years) Dose Formulation Region Male Female 2to≤16 >16to65 >65 Unknown <40 ≥40 Unknown Intravenous Oral EU Japan Colombia US/Canada Other Depression Migraine Table VII. 6 includes interval data obtained from day/month/year throughout day/month/year2165 Table VII.7. Cumulative tabulation of serious adverse events from clinical trials2166 System Organ Class Preferred Term Investigational medicinal product Blinded Active comparator Placebo Blood and lymphatic system disorders Anaemia Bone marrow necrosis Cardiac disorders Tachycardia Ischaemic cardiomyopathy 2167 Table VII.8. Numbers of adverse reactions by preferred term from post-authorisation sources*2168 SOC MedDRA PT Spontaneous, including competent authorities (worldwide) and literature Non-interventional post- marketing study and reports from other solicited sources ** Serious Non-serious Total Spontaneous Serious Interval Cumulative Interval Cumulative Cumulative Interval Cumulative <SOC 1> <PT> <PT> <PT> <SOC 2> <PT> <PT> <PT> <PT> * Non-interventional post-authorisation studies, reports from other solicited sources and spontaneous ICSRs (i.e.,2169 reports from healthcare professionals, consumers, competent authorities (worldwide), and scientific literature)2170 ** This does not include interventional clinical trials.2171
Guideline on good pharmacovigilance practices (GVP) – Module VII EMA/252670/20122 Page 68/69 VII.Appendix 2. Example of tabular summary of safety signals that were2172 ongoing or closed during the reporting interval2173 The tabular summary below is a fictitious example.2174 Table VII.9. Tabular summary of safety signals ongoing or closed during the reporting interval2175 Reporting interval: DD-MMM-YYYY to DD-MMM-YYYY2176 2177
Guideline on good pharmacovigilance practices (GVP) – Module VII EMA/252670/20122 Page 69/69 Explanatory notes:2178 Signal term:2179  A brief descriptive name of a medical concept for the signal. This may evolve and be refined as the2180 signal is evaluated. The concept and scope may or may not be limited to specific MedDRA term(s),2181 depending on the source of signal.2182 Date detected:2183  Month and year the marketing authorisation holder became aware of the signal.2184 Status:2185  Ongoing: Signal under evaluation at the data lock point of the PSUR. Anticipated completion date,2186 if known, should be provided.2187  Closed: Signal for which evaluation was completed before the data lock point of the PSUR.2188 Note: A new signal of which the marketing authorisation holder became aware during the reporting2189 interval may be classified as closed or ongoing, depending on the status of the signal evaluation at the2190 end of the reporting interval of the PSUR.2191 Date closed:2192  Month and year when the signal evaluation was completed.2193 Source of signal:2194  Data or information source from which a signal arose. Examples include, but may not be limited to,2195 spontaneous reports, clinical trial data, scientific literature, and non-clinical study results, or2196 information request or inquiries from a competent authority (worldwide).2197 Reason for evaluation and summary of key data:2198  A brief summary of key data and rationale for further evaluation.2199 Action(s) taken or planned:2200 State whether or not a specific action has been taken or is planned for all closed signals that have been2201 classified as potential or identified risks. If any further actions are planned for newly or previously2202 identified signals under evaluation at the data lock point, these should be listed, otherwise leave blank2203 for ongoing signals.2204

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Eu module VII: PSUR released for public consultation

  • 1. See websites for contact details European Medicines Agency www.ema.europa.eu Heads of Medicines Agencies www.hma.eu The European Medicines Agency is an agency of the European Union © European Medicines Agency and Heads of Medicines Agencies, 2013. Reproduction is authorised provided the source is acknowledged. 19 April 20131 EMA/816292/2011 Rev 1*2 Guideline on good pharmacovigilance practices (GVP)3 Module VII – Periodic safety update report (Rev 1)4 Date for coming into effect of first version 2 July 2012 Draft Revision 1* finalised by the Agency in collaboration with Member States 21 March 2013 Draft Revision 1 agreed by ERMS FG 27 March 2013 Draft Revision 1 adopted by Executive Director 19 April 2013 Released for public consultation 25 April 2013 End of consultation (deadline for comments) 25 June 2013 Revised draft Revision 1 finalised by the Agency in collaboration with Member States Revised draft Revision 1 agreed by ERMS FG Revised draft Revision 1 adopted by Executive Director as final Date for coming into effect of Revision 1 Q 4 2013 5 *Note: Revision 1 contains the following:6 - Updates in VII.B and VII.C.5. following finalisation of the ICH-E2C(R2) guideline on “Periodic Benefit-7 Risk Evaluation Report (PBRER)”, which reached Step 4 of the ICH process in November 2012, in order8 to harmonise the principles and agreements reached by the ICH Expert Working Group;9 - Further guidance regarding technical aspects on the implementation of Regulation (EU) No10 1235/2010 and Directive 2010/84/EU based on the experience gained since July 2012;11 - Practical instructions for the application, description and maintenance of the EU reference date list in12 VII.C.3.2., VII.C.3.3. and VII.C.3.4. and amendments to the marketing authorisation in VII.C.3.7.;13 - Further instructions regarding the PSUR assessment process, product information and transitional14 arrangements within the EU regulatory network in VII.C..15 16 Comments should be provided using this template. The completed comments form should be sent to
  • 2. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 2/69 gvp@ema.europa.eu. 17 Note for public consultation:18 The public consultation is restricted to the yellow highlighted revised texts (i.e. replaced by new texts19 with deletions and additions) or deleted texts (i.e. not replaced). However, if revisions or deletions20 impact or contradict other existing text, comments on such non-highlighted texts will be processed and21 taken into account for the finalisation process. Please note that ICH-E2C(R2) guideline has already22 been subject to public consultation in the EU, and participants in the consultation process are therefore23 asked not to comment on the underlying agreements reached at ICH level.24 25 26
  • 3. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 3/69 TABLE OF CONTENTS27 VII.A. Introduction...................................................................................... 628 VII.B. Structures and processes .................................................................. 729 VII.B.1. Objectives of the periodic update safety report (PSUR) ........................................730 VII.B.2. Principles for the evaluation of the risk-benefit balance within PSURs and scope of31 the information to be included ......................................................................................832 VII.B.3. Principles for the preparation of PSURs ..............................................................933 VII.B.4. Reference information .....................................................................................934 VII.B.5. Format and contents of the PSUR....................................................................1135 VII.B.5.1. PSUR section “Introduction” ........................................................................1436 VII.B.5.2. PSUR section “Worldwide marketing authorisation status" ...............................1437 VII.B.5.3. PSUR section “Actions taken in the reporting interval for safety reasons” ..........1538 VII.B.5.4. PSUR section “Changes to reference safety information” .................................1639 VII.B.5.5. PSUR section “Estimated exposure and use patterns” .....................................1640 VII.B.5.5.1. PSUR sub-section “Cumulative subject exposure in clinical trials” ..................1641 VII.B.5.5.2. PSUR sub-section “Cumulative and interval patient exposure from marketing42 experience”..............................................................................................................1743 VII.B.5.6. PSUR section “Data in summary tabulations” .................................................1844 VII.B.5.6.1. PSUR sub-section “Reference information”..................................................1845 VII.B.5.6.2. PSUR sub-section “Cumulative summary tabulations of serious adverse events46 from clinical trials” ....................................................................................................1947 VII.B.5.6.3. PSUR sub-section “Cumulative and interval summary tabulations from post-48 marketing data sources” ............................................................................................1949 VII.B.5.7. PSUR section “Summaries of significant findings from clinical trials during the50 reporting interval”.....................................................................................................2051 VII.B.5.7.1. PSUR sub-section “Completed clinical trials” ...............................................2152 VII.B.5.7.2. PSUR sub-section “Ongoing clinical trials”...................................................2153 VII.B.5.7.3. PSUR sub-section “Long term follow-up” ....................................................2154 VII.B.5.7.4. PSUR sub-section “Other therapeutic use of medicinal product”.....................2155 VII.B.5.7.5. PSUR sub-section “New safety data related to fixed combination therapies”....2156 VII.B.5.8. PSUR section “Findings from non-interventional studies” .................................2257 VII.B.5.9. PSUR section “Information for other clinical trials and sources” ........................2258 VII.B.5.9 1. PSUR sub-section “Other clinical trials”.......................................................2259 VII.B.5.9 2. PSUR sub-section “Medication errors” ........................................................2260 VII.B.5.10. PSUR section “Non-clinical data”.................................................................2261 VII.B.5.11. PSUR section “Literature” ..........................................................................2362 VII.B.5.12. PSUR section “Other periodic reports” .........................................................2363 VII.B.5.13. PSUR section “Lack of efficacy in controlled clinical trials” ..............................2464 VII.B.5.14. PSUR section “Late-breaking information” ...................................................2465 VII.B.5.15. PSUR section “Overview of signals: new, ongoing, or closed” .........................2466 VII.B.5.16. PSUR section “Signal and risk evaluation”....................................................2567 VII.B.5.16.1. PSUR sub-section “Summary of safety concerns”.......................................2668 VII.B.5.16.2. PSUR sub-section “Signal evaluation”.......................................................2769 VII.B.5.16.3. PSUR sub-section “Evaluation of risks and new information” .......................2870 VII.B.5.16.4. PSUR sub-section “Characterisation of risks” .............................................2971 VII.B.5.16.5. PSUR sub-section: “Effectiveness of risk minimisation (if applicable)”...........3072
  • 4. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 4/69 VII.B.5.17. PSUR section “Benefit evaluation”...............................................................3073 VII.B.5.17.1. PSUR sub-section “Important baseline efficacy and effectiveness information”74 ..............................................................................................................................3075 VII.B.5.17.2. PSUR sub-section “Newly identified information on efficacy and effectiveness”76 ..............................................................................................................................3077 VII.B.5.17.3. PSUR sub-section “Characterisation of benefits” ........................................3178 VII.B.5.18. PSUR section “Integrated benefit-risk analysis for authorised indications”........3179 VII.B.5.18.1. PSUR sub-section “Benefit-risk context - medical need and important80 alternatives”.............................................................................................................3281 VII.B.5.18.2. PSUR sub-section “Benefit-risk analysis evaluation” ...................................3282 VII.B.5.19. PSUR section “Conclusions and actions” ......................................................3383 VII.B.5.20. Appendices to the PSUR ............................................................................3384 VII.B.5.21. Mapping signals and risks to PSUR sections/sub-sections...............................3485 VII.B.6. Quality systems for PSURs at the level of marketing authorisation holders ...........3586 VII.B.7. Training of staff members related to the PSUR process ......................................3687 VII.C. Operation of the EU network ........................................................... 3688 VII.C.1. PSUR process in the EU - General process........................................................3689 VII.C.2. Standard submission schedule of PSURs ..........................................................3890 VII.C.3. List of European Union reference dates and frequency of submission of PSURs .....3891 VII.C.3.1. Objectives of the EU reference dates list .......................................................3892 VII.C.3.2. Description of the EU reference dates list ......................................................3993 VII.C.3.3. Application of the list of EU reference dates to submission of PSURs .................4094 VII.C.3.3.1. Submission of PSURs for medicinal products: general requirement ................4095 VII.C.3.3.2. Submission of PSURs for generic, well-established use, traditional herbal and96 homeopathic medicinal products .................................................................................4197 VII.C.3.3.3. Submission of PSURs for fixed dose combination products ............................4398 VII.C.3.3.4. Submission of PSURs on demand of a competent authority in a Member State 4399 VII.C.3.4. Criteria used for defining the frequency of submission of PSURs.......................43100 VII.C.3.5. Maintenance of the list of EU reference dates.................................................44101 VII.C.3.5.1. General principles....................................................................................44102 VII.C.3.5.2. Requests from marketing authorisation holders to amend the list of EU103 reference dates ........................................................................................................46104 VII.C.3.6. Publication of the list ..................................................................................46105 VII.C.3.7. Amendment of the marketing authorisation according to the list of EU reference106 dates.......................................................................................................................46107 VII.C.4. Processes for PSUR Assessment in the EU network............................................46108 VII.C.4.1. PSURs for purely nationally authorised medicinal products ..............................47109 VII.C.4.2. Medicinal products authorised in more than one Member State ........................48110 VII.C.4.2.1. Assessment of PSURs for a single centrally authorised medicinal product .......48111 VII.C.4.2.2. Assessment of PSURs for medicinal products subject to different marketing112 authorisations containing the same active substance (EU single assessment) ...................51113 VII.C.4.2.3. Single assessment including at least one centrally authorised product leading to114 a CHMP opinion ........................................................................................................54115 VII.C.4.2.4. Single assessment not including centrally authorised product leading to a CMDh116 position ...................................................................................................................56117 VII.C.4.3. Relationship between PSUR and risk management plan...................................57118 VII.C.4.3.1. PSUR and risk management plan – common modules ..................................57119 VII.C.5. EU-specific requirements for periodic safety update reports................................58120
  • 5. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 5/69 VII.C.5.1. PSUR EU regional appendix, sub-section “Proposed product information” ..........58121 VII.C.5.2. PSUR EU regional appendix, sub-section “Proposed additional pharmacovigilance122 and risk minimisation activities”..................................................................................59123 VII.C.5.3. PSUR EU regional appendix, sub-section “Summary of ongoing safety concerns” 59124 VII.C.5.4. PSUR EU regional appendix, sub-section “Reporting of results from post-125 authorisation safety studies” ......................................................................................59126 VII.C.5.5. PSUR EU regional appendix, sub-section “Effectiveness of risk minimisation” .....59127 VII.C.6. Quality systems and record management systems for PSURs in the EU network ...60128 VII.C.6.1. Quality systems and record management systems at the level of the marketing129 authorisation holder ..................................................................................................60130 VII.C.6.2. Quality systems and record management systems at the level of the European131 Medicines Agency......................................................................................................61132 VII.C.6.3. Quality systems and record management systems at the level of the competent133 authorities in Member States......................................................................................62134 VII.C.7. Transparency ...............................................................................................63135 VII.C.7.1. Publication of PSUR-related documents on the European medicines and national136 medicines web-portals...............................................................................................63137 VII.C.8. Renewal of marketing authorisations ...............................................................63138 VII.C.9. Transition and interim arrangements ...............................................................64139 VII.C.9.1. Submission and availability of documents before the Agency’s repository is in140 place.......................................................................................................................64141 VII.C.9.2. Quality systems and record management systems at the level of the competent142 authorities in Member States......................................................................................65143 VII.C.9.3. Publication of the EU list of union references dates and start of the EU-PSUR single144 assessment procedure...............................................................................................65145 VII.APPENDICES ....................................................................................... 66146 VII.Appendix 1. Examples of tabulations for estimated exposure and adverse147 events/reactions data................................................................................................66148 VII.Appendix 2. Example of tabular summary of safety signals that were ongoing or closed149 during the reporting interval.......................................................................................68150 151 152
  • 6. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 6/69 VII.A. Introduction153 Periodic safety update reports (PSURs) are pharmacovigilance documents intended to provide an154 evaluation of the risk-benefit balance of a medicinal product for submission by marketing authorisation155 holders at defined time points during the post-authorisation phase.156 The legal requirements for submission of PSURs are established in Regulation (EC) No 726/2004,157 Directive 2001/83/EC and in the Commission Implementing Regulation (EU) No 520/2012 on the158 performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 and Directive159 2001/83/EC (hereinafter referred to as IR). All applicable legal requirements in this Module are160 referenced in the way explained in the GVP Introductory Cover Note and are usually identifiable by the161 modal verb “shall”. Guidance for the implementation of legal requirements is provided using the modal162 verb “should”.163 The format of PSURs shall follow the structure described in the IR Article 35. This Module provides164 guidance on the preparation, submission and assessment of PSURs.165 The scope, objectives, format and content of the PSUR are described in VII.B.. The required format166 and content of PSURs in the EU are based on those for the Periodic Benefit Risk Evaluation Report167 (PBRER) described in the ICH-E2C(R2) guideline (see Annex IV ICH-E2C(R2)). The PBRER format168 replaces the PSUR format previously described in the ICH-E2C(R1). In line with the EU legislation, the169 report is described as PSUR in the GVP Modules.170 Further details and guidance for the submission of PSURs in the EU, including the list of Union171 references dates and frequency of submission are provided in VII.C., which also covers the single EU172 assessment of PSURs in VII.C.4.. Details related to the quality system are provided in VII.C.6. and the173 publication of PSUR-related documents in VII.C.7. as transparency provisions.174 Each marketing authorisation holder shall be responsible for submitting PSURs for its own products175 [DIR Art 107b] [REG Art 28 (2)] and should submit PSURs to the Agency (see VII.C.9. for transitional176 arrangements) according to the following timelines:177  within 70 calendar days of the data lock point (day 0) for PSURs covering intervals up to 12178 months (including intervals of exactly 12 months); and179  within 90 calendar days of the data lock (day 0) point for PSURs covering intervals in excess of 12180 months;181  the timeline for the submission of ad hoc PSURs requested by competent authorities will normally182 be specified in the request, otherwise the ad hoc PSURs should be submitted within 90 calendar183 days of the data lock point.184 It should be noted that detailed listings of individual cases shall not be included systematically [IR Art185 34(4)]. The PSUR should focus on summary information, scientific safety assessment and integrated186 benefit-risk evaluation.187 Recital 23 of Directive 2010/84/EU explains that the obligations imposed in respect of PSURs should be188 proportionate to the risks posed by medicinal products. PSUR reporting should therefore be linked to189 the risk management systems of a medicinal product (see Module V). The “modular approach” of the190 PSUR described in VII.B.5. aims to minimise duplication and improve efficiency during the preparation191 and review of PSURs along with other regulatory documents such as the development safety update192 report (DSUR)1 or the safety specification in the Risk Management Plan (RMP), by enabling the193 1 See Detailed Guidance on the Collection, Verification and Presentation of Adverse Event/Reaction Reports Arising from Clinical Trials on Medicinal Products for Human Use; available on http://ec.europa.eu/health/documents/eudralex/vol-10/
  • 7. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 7/69 common content of particular sections where appropriate to be utilised interchangeably across different194 PSURs, DSURs and RMPs.195 The 2010 amendment of the legislation also waives the obligation to submit PSURs routinely for196 generic medicinal products (authorised under DIR Art 10(1)), well-established use medicinal products197 (authorised under DIR Art 10a), homeopathic medicinal products (authorised under DIR Art 14) and198 traditional herbal medicinal products (authorised under DIR Art 16a), [DIR Art 107b(3)]. For such199 products, PSURs shall be submitted where there is a condition in the marketing authorisation or when200 requested by a competent authority in a Member State on the basis of concerns relating to201 pharmacovigilance data or due to the lack of PSURs for an active substance after its authorisation [DIR202 Art 107b(3)(a) and (3)(b)].203 Competent authorities in the Member States shall assess PSURs to determine whether there are new204 risks or whether risks have changed or whether there are changes to the risk-benefit balance of205 medicinal products [DIR Art 107d].206 In order to increase the shared use of resources between competent authorities in Member States, a207 single assessment of PSURs should be performed in the EU for different medicinal products containing208 the same active substance or the same combination of active substances authorised in more than one209 Member State for which a Union reference date and frequency of submission of PSURs has been210 established. The EU single assessment can include joint assessment for medicinal products authorised211 through either national or centralised procedures for marketing authorisation. The Agency shall make212 available a list of Union reference dates and frequency of submission [REG Art 26(g)] which will be213 legally binding.214 As part of the assessment, it should be considered whether further investigations need to be carried215 out and whether any action concerning the marketing authorisations of products containing the same216 active substance or the same combination of active substances, and their product information is217 necessary.218 The Agency shall make the PSURs available to the competent authorities in Member States, members219 of the Pharmacovigilance Risk Assessment Committee (PRAC), of the Committee for Medicinal Products220 for Human use (CHMP) and of the Coordination Group for Mutual Recognition and Decentralised221 Procedures - Human (CMDh) and the European Commission by means of a PSUR repository [DIR Art222 107b(2)].223 VII.B. Structures and processes224 VII.B.1. Objectives of the periodic update safety report (PSUR)225 The main objective of a PSUR is to present a comprehensive, concise and critical analysis of the risk-226 benefit balance of the medicinal product taking into account new or emerging information in the227 context of cumulative information on risks and benefits. The PSUR is therefore a tool for post-228 authorisation evaluation at defined time points in the lifecycle of a product.229 For the purposes of lifecycle benefit-risk management, it is necessary to continue evaluating the risks230 and benefits of a medicine in everyday medical practice and long term use in the post-authorisation231 phase. This may extend to evaluation of populations and endpoints that could not be investigated in232 the pre-authorisation clinical trials. A different risk-benefit balance may emerge as pharmacovigilance233 reveals further information about safety. The marketing authorisation holder should therefore re-234 evaluate the risk-benefit balance of its own medicinal products in populations exposed. This structured235 evaluation should be undertaken in the context of ongoing pharmacovigilance (see Module XII) and236
  • 8. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 8/69 risk management (see Module V) to facilitate optimisation of the risk-benefit balance through effective237 risk minimisation.238 A PSUR should not be used to provide initial notification of significant new safety information or, as a239 general rule, provide the means by which new safety issues are detected, or new efficacy data are240 submitted (see Module IX and XII).241 VII.B.2. Principles for the evaluation of the risk-benefit balance within242 PSURs and scope of the information to be included243 Benefit-risk evaluation should be carried out throughout the lifecycle of the medicinal product to244 promote and protect public health and to enhance patient safety through effective risk minimisation.245 After a marketing authorisation is granted, it is necessary to continue evaluating the benefits and risks246 of medicinal products in actual use and/or long term use, to confirm that the risk-benefit balance247 remains favourable.248 The analysis of the risk-benefit balance should incorporate an evaluation of the safety, efficacy and249 effectiveness information that becomes available2 , with reasonable and appropriate effort, during the250 reporting interval for the medicinal product in the context of what was known previously.251 The risk evaluation should be based on all uses of the medicinal product. The scope includes evaluation252 of safety in real medical practice including use in unauthorised indications and use which is not in line253 with the product information. If use of the medicinal product is identified where there are critical gaps254 in knowledge for specific safety issues or populations, such use should be reported in the PSUR (e.g.255 use in paediatric population or in pregnant women). Sources of information on use outside256 authorisation may include drug utilisation data, information from spontaneous reports and publications257 in the literature.258 The scope of the benefit information should include both clinical trial and real world data in authorised259 indications.260 The integrated benefit-risk evaluation should be based on all authorised indications but should261 incorporate the evaluation of risks in all use of the medicinal product (including use in unauthorised262 indications).263 The evaluation should involve:264 1. Critically examining the information which has emerged during the reporting interval to determine265 whether it has generated new signals, led to the identification of new potential or identified risks or266 contributed to knowledge of previously identified risks.267 2. Critically summarising relevant new safety, efficacy and effectiveness information that could have268 an impact on the risk-benefit balance of the medicinal product.269 3. Conducting an integrated benefit-risk analysis for all authorised indications based on the270 cumulative information available since the development international birth date (DIBD), the date of271 first authorisation for the conduct of an interventional clinical trial in any country. For the cases272 where the DIBD is unknown or the marketing authorisation holder does not have access to data273 from the clinical development period, the earliest possible applicable date should be used as274 starting point for the inclusion and evaluation of the cumulative information.275 2 The ICH-E2C(R2) guideline should not serve to limit the scope of the information to be provided in the benefit-risk evaluation of a medicinal product. Please refer to the applicable laws and regulations in the countries and regions. For EU specific requirements, see VII.C.5..
  • 9. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 9/69 4. Summarising any risk minimisation actions that may have been taken or implemented during the276 reporting interval, as well as risk minimisation actions that are planned to be implemented.277 5. Outlining plans for signal or risk evaluations including timelines and/or proposals for additional278 pharmacovigilance activities.279 VII.B.3. Principles for the preparation of PSURs280 Unless otherwise specified by competent authorities, the marketing authorisation holder shall prepare281 a single PSUR for all its medicinal products containing the same active substance with information282 covering all the authorised indications, route of administration, dosage forms and dosing regiments,283 irrespective of whether authorised under different names and through separate procedures. Where284 relevant, data relating to a particular indication, dosage form, route of administration or dosing285 regimen, shall be presented in a separate section of the PSUR and any safety concerns shall be286 addressed accordingly [IR Art 34(6)]. There might be exceptional scenarios where the preparation of287 separate PSURs might be appropriate, for instance, in the event of different formulations for entirely288 different indications. In this case, agreement should be obtained from the relevant competent289 authorities preferably at the time of authorisation.290 Case narratives shall be provided in the relevant risk evaluation section of the PSUR where integral to291 the scientific analysis of a signal or safety concern [IR Art 34(4)]. In this context, the term “case292 narratives” refers to clinical evaluations of individual cases rather than the CIOMS narratives. It should293 not be necessary to provide the actual CIOMS narrative text included in the individual case safety294 report (ICSR) but rather a clinical evaluation of important or illustrative cases in the context of the295 evaluation of the safety concern/signal.296 When data received at the marketing authorisation holder from a partner might contribute297 meaningfully to the safety, benefit and/or benefit-risk analyses and influence the reporting marketing298 authorisation holder’s product information, these data should be included and discussed in the PSUR.299 The format and table of contents of all PSURs shall be as described in the IR Art 35 and each report300 should include interval as well as cumulative data. As the PSUR should be a single stand–alone301 document for the reporting interval, based on cumulative data, summary bridging reports and302 addendum reports, introduced in ICH-E2C(R1) guideline, will not be accepted.303 VII.B.4. Reference information304 Risk minimisation activities evaluated in the PSUR include updates to the product information.305 The reference product information for the PSUR should include “core safety” and “authorised306 indications” components. In order to facilitate the assessment of benefit and risk-benefit balance by307 indication in the evaluation sections of the PSUR, the reference product information document should308 list all authorised indications in ICH countries3 or regions. When the PSUR is also submitted to other309 countries in which there are additional locally authorised indications, these indications may be either310 added to the reference product information or handled as a regional appendix as considered most311 appropriate by the marketing authorization holder. The basis for the benefit evaluation should be the312 baseline important efficacy and effectiveness information summarised in the PSUR section 17.1313 (“Important baseline efficacy and effectiveness information”).314 Information related to a specific indication, formulation or route of administration should be clearly315 identified in the reference product information.316 3 http://www.ich.org/
  • 10. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 10/69 The following possible options can be considered by the marketing authorisation holders when317 selecting the most appropriate reference product information for a PSUR:318  Company core data sheet (CCDS)319  It is common practice for marketing authorisation holders to prepare their own company core320 data sheet which covers data relating to safety, indications, dosing, pharmacology, and other321 information concerning the product. The core safety information contained within the CCDS is322 referred to as the company core safety information (CCSI). A practical option for the purpose323 of the PSUR is for each marketing authorisation holder to use the CCDS in effect at the end of324 the reporting interval, as reference product information for both the risk sections of the PSUR325 as well as the main authorised indications for which benefit is evaluated.326  When the CCDS does not contain information on authorised indications, the marketing327 authorisation holder should clearly specify which document is used as reference information for328 the authorised indications in the PSUR.329  Other options for the reference product information330  When no CCDS or CCSI exist for a product (e.g. where the product is authorised in only one331 country or region, or for established/generics products on the market for many years), the332 marketing authorisation holder should clearly specify the reference information being used.333 This may comprise national or regional product information such as the EU summary of product334 characteristics (SmPC).335  Where the reference information for the authorised indications is a separate document to the336 reference safety information (the core safety information contained within the reference337 product information), the version in effect at the end of the reporting interval should be338 included as an appendix to the PSUR (see VII.B.5.20.).339 The marketing authorisation holder should continuously evaluate whether any revision of the reference340 product information/reference safety information is needed whenever new safety information is341 obtained during the reporting interval and ensure that significant changes made over the interval are342 described in PSUR section 4 (“Changes to the reference safety information”) and where relevant,343 discussed in PSUR section 16 (“Signal and risk evaluation”). These changes may include:344  changes to contraindications, warnings/precautions sections;345  addition to adverse reactions and interactions;346  addition of important new information on use in overdose; and347  removal of an indication or other restrictions for safety or lack of efficacy reasons.348 The marketing authorisation holder should provide a clean copy of all versions of the reference product349 information in effect at the end of the reporting interval (e.g. different formulations included in the350 same PSUR) as an appendix to the PSUR (see VII.B.5.20.). The reference product information should351 be dated and version controlled.352 Where new information on safety that could warrant changes to the authorised product information353 (e.g. new adverse drug reaction, warning or contraindication) has been added to the reference safety354 information during the period from the data lock point to the submission of the PSUR, this information355 should be included in the PSUR section 14 (“Late-breaking information”), if feasible.356 If stipulated by applicable regional requirements, the marketing authorisation holder should provide, in357 the regional appendix, information on any final, ongoing and proposed changes to the national or local358 authorised product information (see VII.C.5.)359
  • 11. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 11/69 The marketing authorisation holder should clearly highlight differences that may have an impact on360 labelling changes (e.g. adverse drug reactions, contraindications, warnings, interactions, overdose)361 between the version of the reference safety information in effect at the end of the reporting interval,362 taking into account any changes made during the late-breaking period, and their proposals for the local363 authorised product information based on the evaluation of the information contained in the PSUR.364 These differences should be included in PSUR regional appendix (see VII.B.5.20. and VII.C.5.2).365 VII.B.5. Format and contents of the PSUR366 The PSUR shall be based on all available data and shall focus on new information which has emerged367 since the data lock point of the last PSUR [IR Art 34(1)]. Cumulative information should be taken into368 account when performing the overall safety evaluation and integrated benefit-risk assessment.369 Because clinical development of a medicinal product frequently continues following marketing370 authorisation, relevant information from post-authorisation studies or clinical trials in unauthorised371 indications or populations should also be included in the PSUR. Similarly, as knowledge of the safety of372 a medicinal product may be derived from evaluation of other data associated with off-label use, such373 knowledge should be reflected in the risk evaluation where relevant and appropriate.374 The PSUR shall provide summaries of data relevant to the benefits and risks of the medicinal product,375 including results of all studies with a consideration of their potential impact on the marketing376 authorisation [DIR Art 107b(1)(a)].377 Examples of sources of efficacy, effectiveness and safety information that may be used in the378 preparation of PSURs include the following:379  non-clinical studies;380  spontaneous reports (e.g. on the marketing authorisation holder’s safety database);381  active surveillance systems (e.g. sentinel sites);382  investigations of product quality;383  product usage data and drug utilisation information;384  clinical trials, including research in unauthorised indications or populations;385  observational studies, including registries;386  patient support programs;387  systematic reviews and meta-analysis;388  marketing authorisation holders sponsored websites4 ;389  published scientific literature or reports from abstracts, including information presented at scientific390 meetings;391  unpublished manuscripts;392  licensing partners, other sponsors or academic institutions and research networks;393  competent authorities (worldwide).394 The above list is not intended to be all inclusive, and additional data sources may be used by the395 marketing authorisation holder to present safety, efficacy and effectiveness in the PSUR and to396 4 ICH-E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting.
  • 12. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 12/69 evaluate the risk-benefit balance, as appropriate to the product and its known and emerging important397 benefits and risks. When desired by the marketing authorisation holder, a list of the sources of398 information used to prepare the PSUR can be provided as an appendix to the PSUR.399 A PSUR shall be prepared following the full modular structure set out in Annex II of the IR [IR Art 35].400 For the purposes of this Module, sources of information include data regarding the active substance(s)401 included in the medicinal product, or the medicinal product that the marketing authorisation holder402 may reasonably be expected to have access to and that are relevant to the evaluation of the safety,403 and/or risk-benefit balance. It is therefore recognised that while the same format (as defined in the IR)404 shall be followed for all products, the extent of the information provided may vary where justified405 according to what is accessible to the marketing authorisation holder. For example, for a marketing406 authorisation holder sponsored clinical trial, there should be access to patient level data while for a407 clinical trial not sponsored by the marketing authorisation holder, only the published report may be408 accessible.409 The level of detail provided in certain sections of the PSUR should depend on known or emerging410 important information on the medicinal product’s benefits and risks. This approach is applicable to411 those sections of the PSUR in which there is evaluation of information about safety, efficacy,412 effectiveness, safety signals and risk-benefit balance.413 When preparing the PSUR, the ICH-E2C(R2) guideline (see Annex IV ICH-E2C(R2)) on PBRER should414 also be applied. Guidance on the titles, order and content of the PSUR sections is provided in VII.B.5.1.415 to VII.B.5.21.. When no relevant information is available for any of the sections, this should be stated.416  Part I: Title page including signature5 417  Part II: Executive Summary418  Part III: Table of Contents419 1. Introduction420 2. Worldwide marketing authorisation status421 3. Actions taken in the reporting interval for safety reasons422 4. Changes to reference safety information423 5. Estimated exposure and use patterns424 5.1. Cumulative subject exposure in clinical trials425 5.2. Cumulative and interval patient exposure from marketing experience426 6. Data in summary tabulations427 6.1. Reference information428 6.2. Cumulative summary tabulations of serious adverse events from clinical trials429 6.3. Cumulative and interval summary tabulations from post-marketing data sources430 7. Summaries of significant findings from clinical trials during the reporting interval431 7.1. Completed clinical trials432 5 For PSURs submission in the EU, it is at the discretion of the QPPV to determine the most appropriate person to sign the document according to the marketing authorisation holder structure and responsibilities. A statement confirming the designation by the QPPV should be included. No delegation letters should be submitted.
  • 13. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 13/69 7.2. Ongoing clinical trials433 7.3. Long-term follow-up434 7.4. Other therapeutic use of medicinal product435 7.5. New safety data related to fixed combination therapies436 8. Findings from non-interventional studies437 9. Information from other clinical trials and sources438 9.1. Other clinical trials439 9.2. Medication errors440 10. Non-clinical Data441 11. Literature442 12. Other periodic reports443 13. Lack of efficacy in controlled clinical trials444 14. Late-breaking information445 15. Overview of signals: new, ongoing or closed446 16. Signal and risk evaluation447 16.1. Summaries of safety concerns448 16.2. Signal evaluation449 16.3. Evaluation of risks and new information450 16.4. Characterisation of risks451 16.5. Effectiveness of risk minimisation (if applicable)452 17. Benefit evaluation453 17.1. Important baseline efficacy and effectiveness information454 17.2. Newly identified information on efficacy and effectiveness455 17.3. Characterisation of benefits456 18. Integrated benefit-risk analysis for authorised indications457 18.1. Benefit-risk context – Medical need and important alternatives458 18.2. Benefit-risk analysis evaluation459 19. Conclusions and actions460 20. Appendices to the PSUR461 PSUR title page462 The title page should include the name of the medicinal product(s)6 and substance, international birth463 date (IBD) (the date of the first marketing authorisation for any product containing the active464 6 For PSURs covering multiple products, for practical reasons, this information may be provided in the PSUR Cover Page (See Annex II)
  • 14. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 14/69 substance granted to any company in any country in the world), reporting interval, date of the report,465 marketing authorisation holder details and statement of confidentiality of the information included in466 the PSUR.467 The title page shall also contain the signature.468 PSUR executive summary469 An executive summary should be placed immediately after the title page and before the table of470 contents. The purpose of the executive summary is to provide a concise summary of the content and471 the most important information in the PSUR and should contain the following information:472  introduction and reporting interval;473  medicinal product(s), therapeutic class(es), mechanism(s) of action, indication(s), pharmaceutical474 formulation(s), dose(s) and route(s) of administration;475  estimated cumulative clinical trials exposure;476  estimated interval and cumulative exposure from marketing experience;477  number of countries in which the medicinal product is authorised;478  summary of the overall benefit-risk analysis evaluation (based on sub-section 18.2 “benefit-risk479 analysis evaluation” of the PSUR);480  actions taken and proposed for safety reasons, (e.g. significant changes to the reference product481 information, or other risk minimisation activities);482  conclusions.483 PSUR table of contents484 The executive summary should be followed by the table of contents.485 VII.B.5.1. PSUR section “Introduction”486 The marketing authorisation holder should briefly introduce the product(s) so that the PSUR “stands487 alone” but it is also placed in perspective relative to previous PSURs and circumstances. The488 introduction should contain the following information:489  IBD, and reporting interval;490  medicinal product(s), therapeutic class(es), mechanism(s) of action, authorised indication(s),491 pharmaceutical form(s), dose(s) and route(s) of administration;492  a brief description of the population(s) being treated and studied;493 VII.B.5.2. PSUR section “Worldwide marketing authorisation status"494 This section of the PSUR should contain a brief narrative overview including: date of the first495 authorisation worldwide, indications(s), authorised dose(s), and where authorised.496
  • 15. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 15/69 VII.B.5.3. PSUR section “Actions taken in the reporting interval for safety497 reasons”498 This section of the PSUR should include a description of significant actions related to safety that have499 been taken worldwide during the reporting interval, related to either investigational uses or marketing500 experience by the marketing authorisation holder, sponsors of clinical trial(s), data monitoring501 committees, ethics committees or competent authorities that had either:502  a significant influence on the risk-benefit balance of the authorised medicinal product; and/or503  an impact on the conduct of a specific clinical trial(s) or on the overall clinical development504 programme.505 If known, the reason for each action should be provided and any additional relevant information should506 be included as appropriate. Relevant updates to previous actions should also be summarised in this507 section.508 Examples of significant actions taken for safety reasons include:509 Actions related to investigational uses:510  refusal to authorise a clinical trial for ethical or safety reasons;511  partial7 or complete clinical trial suspension or early termination of an ongoing clinical trial because512 of safety findings or lack of efficacy;513  recall of investigational drug or comparator;514  failure to obtain marketing authorisation for a tested indication including voluntary withdrawal of a515 marketing authorisation application;516  risk management activities, including:517  protocol modifications due to safety or efficacy concerns (e.g. dosage changes, changes in518 study inclusion/exclusion criteria, intensification of subject monitoring, limitation in trial519 duration);520  restrictions in study population or indications;521  changes to the informed consent document relating to safety concerns;522  formulation changes;523  addition by regulators of a special safety-related reporting requirement;524  issuance of a communication to investigators or healthcare professionals; and525  plans for new studies to address safety concerns.526 Actions related to marketing experience:527  failure to obtain or apply for a marketing authorisation renewal;528  withdrawal or suspension of a marketing authorisation;529  actions taken due to product defects and quality issues;530  suspension of supply by the marketing authorisation holder;531 7 “Partial suspension” might include several actions (e.g. suspension of repeat dose studies, but continuation of single dose studies; suspension of trials in one indication, but continuation in another, and/or suspension of a particular dosing regimen in a trial but continuation of other doses). ICH-E2C(R2) guideline (see Annex IV).
  • 16. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 16/69  risk management activities including:532  significant restrictions on distribution or introduction of other risk minimisation measures;533  significant safety-related changes in labelling documents including restrictions on use or534 population treated;535  communications to health care professionals; and536  new post-marketing study requirement(s) imposed by competent authorities.537 VII.B.5.4. PSUR section “Changes to reference safety information”538 This PSUR section should list any significant changes made to the reference safety information within539 the reporting interval. Such changes might include information relating to contraindications, warnings,540 precautions, serious adverse drug reactions, interactions, important findings from ongoing or541 completed clinical trials and significant non-clinical findings (e.g. carcinogenicity studies). Specific542 information relevant to these changes should be provided in the appropriate sections of the PSUR.543 VII.B.5.5. PSUR section “Estimated exposure and use patterns”544 PSURs shall provide an accurate estimate of the population exposed to the medicinal product, including545 all data relating to the volume of sales and volume of prescriptions. This estimate of exposure shall be546 accompanied by a qualitative and quantitative analysis of actual use, which shall indicate, where547 appropriate, how actual use differs from the indicated use based on all data available to the marketing548 authorisation holder, including the results of observational or drug utilisation studies [IR Art 34 (2)].549 This PSUR section should provide estimates of the size and nature of the population exposed to the550 medicinal product including a brief description of the method(s) used to estimate the subject/patient551 exposure and the limitations of that method.552 Consistent methods for calculating subject/patient exposure should be used across PSURs for the same553 medicinal product. If a change in the method is appropriate, both methods and calculations should be554 provided in the PSUR introducing the change and any important difference between the results using555 the two methods should be highlighted.556 VII.B.5.5.1. PSUR sub-section “Cumulative subject exposure in clinical trials”557 This section of the PSUR should contain the following information on the patients studied in clinical558 trials sponsored by the marketing authorisation holder, if applicable presented in tabular formats:559  cumulative numbers of subjects from ongoing and completed clinical trials exposed to the560 investigational medicinal product, placebo, and/or active comparator(s) since the DIBD. It is561 recognised that for “old products”, detailed data might not available;562  more detailed cumulative subject exposure in clinical trials should be presented if available (e.g.563 sub-grouped by age, sex, and racial/ethnic group for the entire development programme);;564  important differences among trials in dose, routes of administration, or patient populations can be565 noted in the tables, if applicable, or separate tables can be considered;566  if clinical trials have been or are being performed in special populations (e.g. pregnant women;567 patients with renal, hepatic, or cardiac impairment; or patients with relevant genetic568 polymorphisms), exposure data should be provided as appropriate;569
  • 17. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 17/69  when there are substantial differences in time of exposure between subjects randomised to the570 investigational medicinal product or comparator(s), or disparities in length of exposure between571 clinical trials, it can be useful to express exposure in subject-time (subject-days, -months, or -572 years);573  investigational drug exposure in healthy volunteers might be less relevant to the overall safety574 profile, depending on the type of adverse reaction, particularly when subjects are exposed to a575 single dose. Such data can be presented separately with an explanation as appropriate;576  if the serious adverse events from clinical trials are presented by indication in the summary577 tabulations, the patient exposure should also be presented by indication, where available;578  for individual trials of particular importance, demographic characteristics should be provided579 separately.580 Examples of tabular format for the estimated exposure in clinical trials are presented in VII. Appendix581 1, Tables VII.2, VII.3 and VII.4.582 VII.B.5.5.2. PSUR sub-section “Cumulative and interval patient exposure from marketing583 experience”584 Separate estimates should be provided for cumulative exposure (since the IBD), when possible, and585 interval exposure (since the data lock point of the previous PSUR). Although it is recognised that it is586 often difficult to obtain and validate exposure data, the number of patients exposed should be provided587 whenever possible, along with the method(s) used to determine the estimate. Justification should be588 provided if it is not possible to estimate the number of patients exposed. In this case, alternative589 estimates of exposure, if available, should be presented along with the method(s) used to derive them.590 Examples of alternative measures of exposure include patient-days of exposure and number of591 prescriptions. Only if such measures are not available, measures of drug sales, such as tonnage or592 dosage units, may be used. The concept of a defined daily dose may also be used to arrive at patient593 exposure estimates.594 The data should be presented according to the following categories:595 1. Post-authorisation (non-clinical trial) exposure:596 An overall estimation of patient exposure should be provided. In addition, the data should be597 routinely presented by sex, age, indication, dose, formulation and region, where applicable.598 Depending upon the product, other variables may be relevant, such as number of vaccination599 courses, route(s) of administration, and duration of treatment.600 When there are patterns of reports indicating a safety signal, exposure data within relevant601 subgroups should be presented, if possible.602 2. Post-authorisation use in special populations:603 Where post-authorisation use has occurred in special populations, available information regarding604 cumulative patient numbers exposed and the method of calculation should be provided. Sources of605 such data would include non-interventional studies designed to obtain this information, including606 registries. Populations to be considered for discussion include, but might not be limited to:607  paediatric population;608  elderly population;609  pregnant or lactating women;610
  • 18. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 18/69  patients with hepatic and/or renal impairment;611  patients with other relevant co-morbidity;612  patients with disease severity different from that studied in clinical trials;613  sub-populations carrying relevant genetic polymorphism(s);614  populations with specific racial and/or ethnic origins.615 3. Other post-authorisation use:616 If the marketing authorisation holder becomes aware of a pattern of use of the medicinal product,617 which may be regional, considered relevant for the interpretation of safety data, provide a brief618 description thereof. Examples of such patterns of use may include overdose, abuse, misuse and619 use beyond the recommendation(s) in the reference product information (e.g. an anti-epileptic620 drug used for neuropathic pain and/or prophylaxis of migraine headaches). If known, the621 marketing authorisation holder may briefly comment on whether other use beyond the622 recommendation(s) in the reference product information is supported by clinical guidelines, clinical623 trial evidence, or an absence of authorised alternative treatments. If quantitative use information624 is available, it should be provided. For purposes of identifying patterns of use outside the terms of625 the reference product information, the marketing authorisation holder should use the appropriate626 sections of the reference product information that was in effect at the end of the reporting interval627 of the PSUR (e.g. authorised indication, contraindications).628 Examples of tabular format for the estimated exposure from marketing experience are presented in629 VII. Appendix 1, Tables VII.5 and VII.6.630 VII.B.5.6. PSUR section “Data in summary tabulations”631 The objective of this PSUR section is to present safety data through summary tabulations of serious632 adverse events from clinical trials, spontaneous serious and non-serious reactions from marketing633 experience (including reports from healthcare professionals, consumers, scientific literature, competent634 authorities (worldwide)) and serious reactions from non-interventional studies and other non-635 interventional solicited source. At the discretion of the marketing authorisation holder graphical636 displays can be used to illustrate specific aspects of the data when useful to enhance understanding.637 When the Medical Dictionary for Regulatory Activities (MedDRA) terminology is used for coding the638 adverse event/reaction terms, the preferred term (PT) level and system organ class (SOC) should be639 presented in the summary tabulations.640 The seriousness of the adverse events/reactions in the summary tabulations should correspond to the641 seriousness assigned to events/reactions included in the ICSRs using the criteria established in ICH-642 E2A8 (see Annex IV). When serious and non-serious events/reactions are included in the same ICSR,643 the individual seriousness per reaction should be reflected in the summary tabulations. Seriousness644 should not be changed specifically for the preparation of the PSURs.645 VII.B.5.6.1. PSUR sub-section “Reference information”646 This sub-section of the PSUR should specify the version(s) of the coding dictionary used for647 presentation of adverse events/reactions.648 8 ICH Topic E2A. Clinical safety data management: Definitions and standards for expedited reporting.
  • 19. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 19/69 VII.B.5.6.2. PSUR sub-section “Cumulative summary tabulations of serious adverse events649 from clinical trials”650 This PSUR sub-section should provide background for the appendix that provides a cumulative651 summary tabulation of serious adverse events reported in the marketing authorisation holder’s clinical652 trials, from the DIBD to the data lock point of the current PSUR. The marketing authorisation holder653 should explain any omission of data (e.g. clinical trial data might not be available for products654 marketed for many years). The tabulation(s) should be organised by MedDRA SOC (listed in the655 internationally agreed order), for the investigational drug, as well as for the comparator arm(s) (active656 comparators, placebo) used in the clinical development programme. Data can be integrated across the657 programme. Alternatively, when useful and feasible, data can be presented by trial, indication, route of658 administration or other variables.659 This sub-section should not serve to provide analyses or conclusions based on the serious adverse660 events.661 The following points should be considered:662  Causality assessment is generally useful for the evaluation of individual rare adverse drug663 reactions. Individual case causality assessment has less value in the analysis of aggregate data,664 where group comparisons of rates are possible. Therefore, the summary tabulations should include665 all serious adverse events and not just serious adverse reactions for the investigational drug,666 comparators and placebo. It may be useful to give rates by dose.667  In general, the tabulation(s) of serious adverse events from clinical trials should include only those668 terms that were used in defining the case as serious and non-serious events should be included in669 the study reports.670  The tabulations should include blinded and unblinded clinical trial data. Unblinded serious adverse671 events might originate from completed trials and individual cases that have been unblinded for672 safety-related reasons (e.g. expedited reporting), if applicable. Sponsors of clinical trials and673 marketing authorisation holders should not unblind data for the specific purpose of preparing the674 PSUR.675  Certain adverse events can be excluded from the clinical trials summary tabulations, but such676 exclusions should be explained in the report. For example, adverse events that have been defined677 in the protocol as “exempt” from special collection and entry into the safety database because they678 are anticipated in the patient population, and those that represent study endpoints, can be679 excluded (e.g. deaths reported in a trial of a drug for congestive heart failure where all-cause680 mortality is the primary efficacy endpoint, disease progression in cancer trials).681 An example of summary tabulation of serious adverse events from clinical trials can be found in VII.682 Appendix 1 Table VII.7.683 VII.B.5.6.3. PSUR sub-section “Cumulative and interval summary tabulations from post-684 marketing data sources”685 This sub-section of the PSUR should provide background for the appendix that provides cumulative and686 interval summary tabulations of adverse reactions, from the IBD to the data lock point of the current687 PSUR. These adverse reactions are derived from spontaneous ICSRs including reports from healthcare688 professionals, consumers, scientific literature, competent authorities (worldwide) and from solicited689 non-interventional ICSRs including those from non-interventional studies9 . Serious and non-serious690 reactions from spontaneous sources, as well as serious adverse reactions from non-interventional691 9 ICH-E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting.
  • 20. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 20/69 studies and other non-interventional solicited sources should be presented in a single table, with692 interval and cumulative data presented side-by-side. The table should be organised by MedDRA SOC693 (listed in the internationally agreed order). For special issues or concerns, additional tabulations of694 adverse reactions can be presented by indication, route of administration, or other variables.695 As described in ICH-E2D10 (see Annex IV) guideline, for marketed medicinal products, spontaneously696 reported adverse events usually imply at least a suspicion of causality by the reporter and should be697 considered to be suspected adverse reactions for regulatory reporting purposes.698 Analysis or conclusions based on the summary tabulations should not be provided in this PSUR sub-699 section.700 An example of summary tabulations of adverse drug reactions from post-marketing data sources can701 be found in VII. Appendix 1 Table VII.8.702 VII.B.5.7. PSUR section “Summaries of significant findings from clinical703 trials during the reporting interval”704 This PSUR section should provide a summary of the clinically important emerging efficacy and safety705 findings obtained from the marketing authorisation holder’s sponsored clinical trials during the706 reporting interval, from the sources specified in the sub-sections listed below. When possible and707 relevant, data categorised by sex and age (particularly paediatrics versus adults), indication, dose, and708 region should be presented.709 Signals arising from clinical trial sources should be tabulated in PSUR section 15 (“Overview on signals:710 new, ongoing or closed”). Evaluation of the signals, whether or not categorised as refuted signals or711 either potential or identified risk, that were closed during the reporting interval should be presented in712 PSUR section 16.2 (“Signal evaluation”). New information in relation to any previously known potential713 or identified risks and not considered to constitute a newly identified signal should be evaluated and714 characterised in PSUR sections 16.3 (“Evaluation of risks and new information”) and 16.4715 (“Characterisation of risks”) respectively.716 Findings from clinical trials not sponsored by the marketing authorisation holder should be described in717 the relevant sections of the PSUR.718 When relevant to the benefit-risk evaluation, information on lack of efficacy from clinical trials for719 treatments of non-life-threatening diseases in authorised indications should also be summarised in this720 section. Information on lack of efficacy from clinical trials with products intended to treat or prevent721 serious or life-threatening illness should be summarised in section 13 (“Lack of efficacy in controlled722 clinical trials”).723 In addition, the marketing authorisation holder should include an appendix listing the sponsored post-724 authorisation interventional trials with the primary aim of identifying, characterising, or quantifying a725 safety hazard or confirming the safety profile of the medicinal product that were completed or ongoing726 during the reporting interval. The listing should include the following information for each trial:727  study ID (e.g. protocol number or other identifier);728  study title (abbreviated study title, if applicable);729  study type (e.g. randomised clinical trial, cohort study, case-control study);730  population studied, including country and other relevant population descriptors (e.g. paediatric731 population or trial subjects with impaired renal function);732 10 See footnote 8.
  • 21. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 21/69  study start (as defined by the marketing authorisation holder) and projected completion dates;733  status: ongoing (clinical trial has begun) or completed (clinical study report is finalised).734 VII.B.5.7.1. PSUR sub-section “Completed clinical trials”735 This sub-section of the PSUR should provide a brief summary of clinically important emerging efficacy736 and safety findings obtained from clinical trials completed during the reporting interval. This737 information can be presented in narrative format or as a synopsis11 . It could include information that738 supports or refutes previously identified safety concerns as well as evidence of new safety signals.739 VII.B.5.7.2. PSUR sub-section “Ongoing clinical trials”740 If the marketing authorisation holder is aware of clinically important information that has arisen from741 ongoing clinical trials (e.g. learned through interim safety analyses or as a result of unblinding of742 subjects with adverse events), this sub-section should briefly summarise the concern(s). It could743 include information that supports or refutes previously identified safety concerns, as well as evidence744 of new safety signals.745 VII.B.5.7.3. PSUR sub-section “Long term follow-up”746 Where applicable, this sub-section should provide information from long-term follow-up of subjects747 from clinical trials of investigational drugs, particularly advanced therapy products (e.g. gene therapy,748 cell therapy products and tissue engineered products).749 VII.B.5.7.4. PSUR sub-section “Other therapeutic use of medicinal product”750 This sub-section of the PSUR should include clinically important safety information from other751 programmes conducted by the marketing authorisation holder that follow a specific protocol, with752 solicited reporting as per ICH-E2D12 (e.g. expanded access programmes, compassionate use753 programmes, particular patient use, and other organised data collection).754 VII.B.5.7.5. PSUR sub-section “New safety data related to fixed combination therapies”755 Unless otherwise specified by national or regional regulatory requirements, the following options can756 be used to present data from combination therapies:757  If the active substance that is the subject of the PSURs is also authorised or under development as758 a component of a fixed combination product or a multi-drug regimen, this sub-section should759 summarise important safety findings from use of the combination therapy.760  If the product itself is a fixed combination product, this PSUR sub-section should summarise761 important safety information arising from the individual components whether authorised or under762 development.763 The information specific to the combination can be incorporated into a separate section(s) of the PSUR764 for one or all of the individual components of the combination.765 11 Examples of synopses can be found in ICH-E3: Structure and Content of Clinical Study Reports and CIOMS VII (Council for International Organizations of Medical Sciences (CIOMS). Development Safety Update Report (DSUR): Harmonizing the Format and Content for Periodic Safety Reporting During Clinical Trials - Report of CIOMS Working Group VII). Geneva: CIOMS; 2006. http://www.cioms.ch/. 12 ICH-E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting.
  • 22. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 22/69 VII.B.5.8. PSUR section “Findings from non-interventional studies”766 This section should also summarise relevant safety information or information with potential impact in767 the benefit-risk assessment from marketing authorisation holder-sponsored non-interventional studies768 that became available during the reporting interval (e.g. observational studies, epidemiological studies,769 registries, and active surveillance programmes). This should include relevant information from drug770 utilisation studies when relevant to multiple regions (see VII.B.5.7. for the information that should be771 included in the listing)772 The marketing authorisation holder should include an appendix listing marketing authorisation holder-773 sponsored non-interventional studies conducted with the primary aim of identifying, characterising or774 quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the775 effectiveness of risk management measures which were completed or ongoing during the reporting776 interval.777 Final study reports completed during the reporting interval for the studies mentioned in the paragraph778 above should also be included in the regional appendix of the PSUR (see VII.B.5.20. and VII.C.5.4.).779 VII.B.5.9. PSUR section “Information for other clinical trials and sources”780 Other sources of information may include data collection outside of a study environment. Information781 obtained from reports of events or patterns of use which do not result in suspected adverse reactions782 may be included in sub-sections VII.B.5.9.1. and VII.B.5.9.2. For example, this would include available783 information on reports of asymptomatic overdose, abuse, use beyond that recommended in the784 reference product information, or use in special populations (see Module VI). Such information may be785 received via spontaneous reports, medical information queries, customer’s complaints, screening of786 digital media or via other information sources available to the marketing authorisation holder.787 Signals or risks identified from any information source and/or category of reports should be presented788 and evaluated in the relevant sections of the PSUR.789 VII.B.5.9 1. PSUR sub-section “Other clinical trials”790 This PSUR sub-section should summarise information relevant to the benefit-risk assessment of the791 medicinal product from other clinical trial/study sources, including patient support programs, which are792 accessible by the marketing authorisation holder during the reporting interval (e.g. results from pool793 analysis or meta-analysis of randomised clinical trials, safety information provided by co-development794 partners or from investigator-initiated trials).795 VII.B.5.9 2. PSUR sub-section “Medication errors”796 This sub-section should summarise relevant information on patterns of medication errors and potential797 medication errors, even when not associated with adverse outcomes. A potential medication error is798 the recognition of circumstances that could lead to a medication error, and may or may not involve a799 patient. Such information may be relevant to the interpretation of safety data or the overall benefit-800 risk evaluation of the medicinal product. A medication error may arise at any stage in the medication801 use process and may involve patients, consumers, or healthcare professionals.802 VII.B.5.10. PSUR section “Non-clinical data”803 This PSUR section should summarise major safety findings from non-clinical in vivo and in vitro studies804 (e.g. carcinogenicity, reproduction or immunotoxicity studies) ongoing or completed during the805 reporting interval. Results from studies designated to address specific safety concerns should be806
  • 23. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 23/69 included in the PSUR, regardless of the outcome. Implications of these findings should be discussed in807 the relevant evaluation sections of the PSUR.808 VII.B.5.11. PSUR section “Literature”809 This PSUR section should include a summary of new and significant safety findings, either published in810 the peer-reviewed scientific literature or made available as unpublished manuscripts that the811 marketing authorisation holder became aware of during the reporting interval, when relevant to the812 medicinal product.813 Literature searches for PSURs should be wider than those for individual adverse reaction cases as they814 should also include studies reporting safety outcomes in groups of subjects and other products815 containing the same active substance.816 The special types of safety information that should be included, but which may not be found by a817 search constructed specifically to identify individual cases, include:818  pregnancy outcomes (including termination) with no adverse outcomes;819  use in paediatric populations;820  compassionate supply, named patient use;821  lack of efficacy;822  asymptomatic overdose, abuse or misuse;823  medication error where no adverse events occurred;824  important non-clinical safety results.825 If relevant and applicable, information on other active substances of the same class should be826 considered.827 The publication reference should be provided in the style of the Vancouver Convention13,14 .828 VII.B.5.12. PSUR section “Other periodic reports”829 This PSUR section will only apply in certain circumstances concerning fixed combination products or830 products with multiple indications and/or formulations where multiple PSURs are prepared in831 agreement with the competent authority. In general, the marketing authorisation holder should832 prepare a single PSUR for a single active substance (unless otherwise specified by the competent833 authority); however if multiple PSURs are prepared for a single medicinal product, this section should834 also summarise significant findings from other PSURs if they are not presented elsewhere within the835 report.836 When available, based on the contractual agreements, the marketing authorisation holder should837 summarise significant findings from periodic reports provided during the reporting interval by other838 parties (e.g. sponsors, other marketing authorisation holders or other contractual partners).839 13 Uniform requirements for manuscripts submitted to biomedical journals. International Committee of Medical Journal Editors. N Engl J Med. 1997 Jan 23;336(4):309-15. Available online: http://www.nejm.org/doi/full/10.1056/NEJM199701233360422 14 Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication [Updated April 2010] Publication Ethics: Sponsorship, Authorship, and Accountability, International Committee of Medical Journal Editors. http://www.icmje.org/urm_full.pdf
  • 24. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 24/69 VII.B.5.13. PSUR section “Lack of efficacy in controlled clinical trials”840 This section should summarise data from clinical trials indicating lack of efficacy or lack of efficacy841 relative to established therapy(ies) for products intended to treat or prevent serious or life-threatening842 illnesses (e.g. excess cardiovascular adverse events in a trial of a new anti-platelet medicine for acute843 coronary syndromes) that could reflect a significant risk to the treated population.844 VII.B.5.14. PSUR section “Late-breaking information”845 The marketing authorisation holder should summarise in this PSUR section the potentially important846 safety, efficacy and effectiveness findings that arise after the data lock point but during the period of847 preparation of the PSUR. Examples include clinically significant new publications, important follow-up848 data, clinically relevant toxicological findings and any action that the marketing authorisation holder, a849 data monitoring committee, or a competent authority (worldwide) has taken for safety reasons. New850 individual case reports should not be routinely included unless they are considered to constitute an851 important index case (i.e. the first instance of an important event) or an important safety signal or852 where they may add information to the evaluation of safety concerns already presented in the PSUR853 (e.g. a well documented case of aplastic anaemia in a medicinal product known to be associated with854 adverse effects on the bone marrow in the absence of possible alternative causes).855 Any significant change proposed to the reference product information (e.g. new adverse reaction,856 warning or contraindication) which has occurred during this period, should also be included in this857 section of the PSUR (see VII.B.4.), where feasible.858 The data presented in this section should also be taken into account in the evaluation of risks and new859 information (see VII.B.5.16.3.).860 VII.B.5.15. PSUR section “Overview of signals: new, ongoing, or closed”861 The general location for presentation of information on signals and risks within the PSUR is shown in862 figure 1 (see VII.B.21.). The purpose of this section is to provide a high level overview of signals15 that863 were closed (i.e., evaluation was completed) during the reporting interval as well as ongoing signals864 that were undergoing evaluation at the end of the reporting interval. For the purposes of the PSUR, a865 signal should be included once it has undergone the initial screening or clarification step, and a866 determination made to conduct further evaluation by the marketing authorisation holder16 .It should be867 noted that a safety signal is not synonymous with a statistic of disproportionate reporting for a specific868 medicine/event combination as a validation step is required. Signals may be qualitative (e.g., a pivotal869 individual case safety report, case series) or quantitative (e.g. a disproportionality score, findings of a870 clinical trial or epidemiological study). Signals may arise in the form of an information request or871 inquiry on a safety issue from a competent authority (worldwide) (see Module IX).872 Decisions regarding the subsequent classification of these signals and the conclusions of the873 evaluation, involve medical judgement and scientific interpretation of available data, which is874 presented in section 16 (“Signal and risk evaluation”) of the PSUR.875 A new signal refers to a signal that has been identified during the reporting interval. Where new876 clinically significant information on a previously closed signal becomes available during the reporting877 interval of the PSUR, this would also be considered a new signal on the basis that a new aspect of a878 15 “Signal” means information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action [IR Art 19(1)]. 16 In the EU-regulatory network and for the purpose of the PSUR, the term “signal” in this section corresponds with the term “validated signal” described in GVP Module IX
  • 25. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 25/69 previously refuted signal or recognised risk warrants further action to verify. New signals may be879 classified as closed or ongoing, depending on the status of signal evaluation at the end of the reporting880 interval of the PSUR.881 Examples of new signals would therefore include new information on a previously:882  Close and refuted signal, which would result in the signal being re-opened.883  Identified risk where the new information suggests a clinically significant difference in the severity884 or frequency of the risk (e.g. transient liver enzyme increases are identified risks and new885 information indicative of a more severe outcome such as hepatic failure is received, or neutropenia886 is an identified risk and a well documented case report of agranulocytosis with no presence of887 possible alternative causes is received).888  Identified risk for which a higher frequency or severity of the risk is newly found (e.g. in an889 indicated subpopulation).890  Potential risk which, if confirmed, would warrant a new warning, precaution, a new contraindication891 or restriction in indication(s) or population or other risk minimisation activities.892 Within this section, or as an appendix the marketing authorisation holder should provide a tabulation893 of all signals ongoing or closed at the end of the reporting interval. This tabulation should include the894 following information:895  a brief description of the signal;896  date when the marketing authorisation holder became aware of the signal;897  status of the signal at the end of the reporting interval (close or ongoing);898  date when the signal was closed, if applicable;899  source of the signal;900  a brief summary of the key data;901  plans for further evaluation; and902  actions taken or planned.903 And example of tabulation of signals can be found in VII. Appendix 2.904 The detailed signal assessments for closed signals are not to be included in this section but instead905 should be presented in sub-section 16.2 (“Signal evaluation”) of the PSUR.906 Evaluation of new information in relation to any previously known identified and potential risks and not907 considered to constitute a new signal should be provided in PSUR sub-section 16.3 (“Evaluation of risks908 and new information”).909 When a competent authority (worldwide) has requested that a specific topic (not considered a signal)910 be monitored and reported in a PSUR, the marketing authorisation holder should summarise the result911 of the analysis in this section if it is negative. If the specific topic becomes a signal, it should be912 included in the signal tabulation and discussed in sub-section 16.2 (“Signal evaluation”).913 VII.B.5.16. PSUR section “Signal and risk evaluation”914 The purpose of this section of the PSUR is to provide:915
  • 26. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 26/69  A succinct summary of what is known about important identified and potential risks and important916 missing information at the beginning of the reporting interval covered by the report917 (VII.B.5.16.1.).918  An evaluation of all signals closed during the reporting interval (VII.B.5.16.2.).919  An evaluation of new information with respect to previously recognised identified and potential920 risks (VII.B.5.16.3).921  An updated characterisation of important potential and identified risks, where applicable922 (VII.B.5.16.4.).923  A summary of the effectiveness of risk minimisation activities in any country or region which may924 have utility in other countries or regions (VII.B.5.16.5.).925 A flowchart illustrating the mapping of signals and risks to specific sections/sub-sections of the PSUR926 can be found in VII.B.5.21..927 These evaluation sub-sections should not summarise or duplicate information presented in previous928 sections of the PSUR but should rather provide interpretation and critical appraisal of the information,929 with a view towards characterising the profile of those risks assessed as important. In addition, as a930 general rule, it is not necessary to include individual case narratives in the evaluation sections of the931 PSUR but where integral to the scientific analysis of a signal or risk, a clinical evaluation of pivotal or932 illustrative cases (e.g. the first case of suspected agranulocytosis with an active substance belonging to933 a class known to be associated with this adverse reaction) should be provided (see VII.B.3.).934 VII.B.5.16.1. PSUR sub-section “Summary of safety concerns”935 The purpose of this sub-section is to provide a summary of important safety concerns at the beginning936 of the reporting interval, against which new information and evaluations can be made. For products937 with an existing safety specification, this section can be either the same as, or derived from the safety938 specification summary17 that is current at the start of the reporting interval of the PSUR. It should939 provide the following safety information:940  important identified risks;941  important potential risks; and942  important missing information.943 The following factors should be considered when determining the importance of each risk:944  medical seriousness of the risk, including the impact on individual patients;945  its frequency, predictability, preventability, and reversibility;946  potential impact on public health (frequency; size of treated population); and947  potential for avoidance of the use of a medicinal product with a preventive benefit due to a948 disproportionate public perception of risk (e.g. vaccines).949 For products without an existing safety specification, this section should provide information on the950 important identified and potential risks and important missing information associated with use of the951 product, based on pre- and post-authorisation experience. Important identified and potential risks may952 include, for example:953  important adverse reactions;954 17 ICH-E2E – Pharmacovigilance planning (see Annex IV).
  • 27. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 27/69  interactions with other medicinal products;955  interactions with foods and other substances;956  medication errors;957  effects of occupational exposure; and958  pharmacological class effects.959 The summary on important missing information should take into account whether there are critical960 gaps in knowledge for specific safety issues or populations that use the medicinal product.961 VII.B.5.16.2. PSUR sub-section “Signal evaluation”962 This sub-section of the PSUR should summarise the results of evaluations of all safety signals (whether963 or not classified as important) that were closed during the reporting interval. A safety signal can be964 closed either because it is refuted or because it is determined to be a potential or identified risk,965 following evaluation. The two main categories to be included in this sub-section are:966 1. Those signals that, following evaluation, have been refuted as “false” signals based on medical967 judgement and scientific evaluation of the currently available information.968 2. Those signals that, following evaluation, have been categorised as either a potential or identified969 risk, including lack of efficacy.970 For both categories of closed signals, a concise description of each signal evaluation should be included971 in order to clearly describe the basis upon which the signal was either refuted or considered to be a972 potential or identified risk by the marketing authorisation holder.973 It is recommended that the level of detail provided in the description of the signal evaluation should974 reflect the medical significance of the signal (e.g. severe, irreversible, lead to increased morbidity or975 mortality) and potential public health importance (e.g. wide usage, frequency, significant use outside976 the recommendations of the product information) and the extent of the available evidence. Where977 multiple evaluations will be included under both categories of closed signals, they can be presented in978 the following order:979  Closed and refuted signals.980  Closed signals that are categorised as important potential risks.981  Closed signals that are categorised as important identified risks.982  Closed signals that are potential risks not categorised as important.983  Closed signals that are identified risks not categorised as important.984 Where applicable the evaluations of closed signals can be presented by indication or population.985 The description(s) of the signal evaluations can be included in this sub-section of the PSUR or in an986 appendix. Each evaluation should include the following information as appropriate:987  source or trigger of the signal;988  background relevant to the evaluation;989  method(s) of evaluation, including data sources, search criteria (where applicable, the specific990 MedDRA terms (e.g. PTs, HLTs, SOCs, etc.) or Standardised MedDRA Queries (SMQs) that were991 reviewed), and analytical approaches;992
  • 28. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 28/69  results - a summary and critical analysis of the data considered in the signal evaluation; where993 integral to the assessment, this may include a description of a case series or an individual case994 (e.g. an index case of well documented agranulocytosis or Stevens Johnson Syndrome);995  discussion;996  conclusion.997 VII.B.5.16.3. PSUR sub-section “Evaluation of risks and new information”998 This sub-section should provide a critical appraisal of new information relevant to previously999 recognised risks that is not already included in sub-section 16.2 (“Signal evaluation”).1000 New information that constitutes a signal with respect to a previously recognised risk or previously1001 refuted signal should be presented in the signals tabulation (see VII.B.5.15.) and evaluated in sub-1002 section 16.2 (“Signal evaluation”), if the signal is also closed during the reporting interval of the PSUR1003 Updated information on a previously recognised risk that does not constitute a signal should be1004 included in this sub-section. Examples includes information that confirms a potential risk as an1005 identified risk,1006 or information which allows any other further characterisation of a previously recognised risk.1007 New information can be organised as follows:1008 1. New information on important potential risks.1009 2. New information on important identified risks.1010 3. New information on other potential risks not categorised as important.1011 4. New information on other identified risks not categorised as important.1012 5. Update on important missing information.1013 The focus of the evaluation(s) is on new information which has emerged during the reporting interval1014 of the PSUR. This should be concise and interpret the impact, if any, on the understanding and1015 characterisation of the risk. Where applicable, the evaluation will form the basis for an updated1016 characterisation of important potential and identified risks in sub-section 16.4 (“Characterisation of1017 risks”) of the report. It is recommended that the level of detail of the evaluation included in this sub-1018 section should be proportional to the available evidence on the risk and its medical significance and1019 public health relevance.1020 The evaluation(s) of the new information and missing information update(s) can be included in this1021 sub-section of the PSUR, or in an appendix. Each evaluation should include the following information as1022 appropriate:1023  source of the new information;1024  background relevant to the evaluation;1025  method(s) of evaluation, including data sources, search criteria, and analytical approaches;1026  results – a summary and critical analysis of the data considered in the risk evaluation;1027  discussion;1028  conclusion, including whether or not the evaluation supports an update of the characterisation of1029 any of the important potential and identified risks in sub-section 16.4 (“Characterisation of risks”)1030
  • 29. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 29/69 Any new information on populations exposed or data generated to address previously missing1031 information should be critically assessed in this sub-section. Unresolved concerns and uncertainties1032 should be acknowledged.1033 VII.B.5.16.4. PSUR sub-section “Characterisation of risks”1034 This sub-section should characterise important identified and potential risks based on cumulative data1035 (i.e., not restricted to the reporting interval), and describe important missing information.1036 Depending on the nature of the data source, the characterisation of risk may include, where applicable:1037  frequency;1038  numbers of cases (numerator) and precision of estimate, taking into account the source of the1039 data;1040  extent of use (denominator) expressed as numbers of patients, patient-time, etc., and precision of1041 estimate;1042  estimate of relative risk and precision of estimate;1043  estimate of absolute risk and precision of estimate;1044  impact on the individual patient (effects on symptoms, quality or quantity of life);1045  public health impact;1046  patient characteristics relevant to risk (e.g. patient factors (age, pregnancy/lactation, hepatic/renal1047 impairment, relevant co-morbidity, disease severity, genetic polymorphism);1048  dose, route of administration;1049  duration of treatment, risk period;1050  preventability (i.e. predictability, ability to monitor for a “sentinel” adverse reaction or laboratory1051 marker);1052  reversibility;1053  potential mechanism; and1054  strength of evidence and its uncertainties, including analysis of conflicting evidence, if applicable.1055 When missing information could constitute an important risk, it should be included as a safety concern.1056 The limitations of the safety database (in terms of number of patients studied, cumulative exposure or1057 long term use, etc.) should be discussed.1058 For PSURs for products with several indications, formulations, or routes of administration, where there1059 may be significant differences in the identified and potential risks, it may be appropriate to present1060 risks by indication, formulation, or route of administration. Headings that could be considered include:1061  risks relating to the active substance;1062  risks related to a specific formulation or route of administration (including occupational exposure);1063  risks relating to a specific population;1064  risks associated with non-prescription use (for compounds that are available as both prescription1065 and non-prescription products); and1066
  • 30. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 30/69 VII.B.5.16.5. PSUR sub-section: “Effectiveness of risk minimisation (if applicable)”1067 Risk minimisation activities are public health interventions intended to prevent the occurrence of an1068 adverse drug reaction(s) associated with the exposure to a medicinal product or to reduce its severity1069 should it occur. The aim of a risk minimisation activity is to reduce the probability or severity of an1070 adverse drug reaction. Risk minimisation activities may consist of routine risk minimisation (e.g.1071 product labelling) or additional risk minimisation activities (e.g. Direct Healthcare Professional1072 Communication/educational materials).1073 The PSUR shall contain the results of assessments of the effectiveness of risk minimisation activities1074 relevant to the risk-benefit assessment [IR Art 34(3)].1075 Relevant information on the effectiveness and/or limitations of specific risk minimisation activities for1076 important identified risks that has become available during the reporting interval should be1077 summarised in this sub-section of the PSUR.1078 Insights into the effectiveness of risk minimisation activities in any country or region that may have1079 utility in other countries or regions are of particular interest. Information may be summarised by1080 region, if applicable and relevant.1081 When required for reporting in a PSUR, results of evaluations that became available during the1082 reporting interval, which refer to an individual region should be provided in the PSUR regional appendix1083 (see VII.B.5.20. and VII.C.5.5.).1084 VII.B.5.17. PSUR section “Benefit evaluation”1085 PSUR sub-sections 17.1 (“Important baseline efficacy and effectiveness information”) and 17.2 (“Newly1086 identified information on efficacy and effectiveness”) provide the baseline and newly identified benefit1087 information that support the characterisation of benefit described in sub-section 17.31088 (“Characterisation of benefits”) that in turn supports the benefit-risk evaluation in section 181089 (“Integrated benefit-risk analysis for authorised indications”).1090 VII.B.5.17.1. PSUR sub-section “Important baseline efficacy and effectiveness information”1091 This sub-section of the PSUR summarises information on both efficacy and effectiveness of the1092 medicinal product at the beginning of the reporting interval and provides the basis for the benefit1093 evaluation. This information should relate to authorised indication(s) of the medicinal product listed in1094 the reference product information (See VII.B.4.) .1095 For medicinal products with multiple indications, populations, and/or routes of administration, the1096 benefit should be characterised separately by these factors when relevant.1097 The level of detail provided in this sub-section should be sufficient to support the characterisation of1098 benefit in the PSUR sub-section 17.3 (“Characterisation of benefits”) and the benefit-risk assessment1099 in section 18 (“Integrated benefit-risk analysis for authorised indications”).1100 VII.B.5.17.2. PSUR sub-section “Newly identified information on efficacy and effectiveness”1101 For some products, additional information on efficacy or effectiveness in authorised indications may1102 have become available during the reporting interval. Such information should be presented in this sub-1103 section of the PSUR. For authorised indications, new information on efficacy and effectiveness under1104 conditions of actual use should also be described in this sub-section, if available. New information on1105 efficacy and effectiveness in uses other than the authorised indications should not be included unless1106 relevant for the benefit-risk evaluation in the authorised indications.1107
  • 31. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 31/69 Information on indications newly authorised during the reporting interval should also be included in1108 this sub-section. The level of detail provided in this section should be sufficient to support the1109 characterisation of benefit in sub-section 17.3 (“Characterisation of benefits”) and the benefit-risk1110 assessment in section 18 (“Integrated benefit-risk analysis for authorised indications”).1111 In this sub-section, particular attention should be given to vaccines, anti-infective agents or other1112 medicinal products where changes in the therapeutic environment may impact on1113 efficacy/effectiveness over time.1114 VII.B.5.17.3. PSUR sub-section “Characterisation of benefits”1115 This sub-section provides an integration of the baseline benefit information and the new benefit1116 information that has become available during the reporting interval, for authorised indications.1117 The level of detail provided in this sub-section should be sufficient to support the analysis of benefit-1118 risk in section 18 (“Integrated benefit-risk analysis for authorised indications”).1119 When there are no new relevant benefit data, this sub-section should provide a characterisation of the1120 information in sub-section 17.1 (“Important baseline efficacy and effectiveness information”).1121 When there is new positive benefit information and no significant change in the risk profile in this1122 reporting interval, the integration of baseline and new information in this sub-section should be1123 succinct.1124 This sub-section should provide a concise but critical evaluation of the strengths and limitations of the1125 evidence on efficacy and effectiveness, considering the following when available:1126  a brief description of the strength of evidence of benefit, considering comparator(s), effect size,1127 statistical rigor, methodological strengths and deficiencies, and consistency of findings across1128 trials/studies;1129  new information that challenges the validity of a surrogate endpoint, if used;1130  clinical relevance of the effect size;1131  generalisability of treatment response across the indicated patient population (e.g. information that1132 demonstrates lack of treatment effect in a sub-population);1133  adequacy of characterization of dose-response;1134  duration of effect;1135  comparative efficacy; and1136  a determination of the extent to which efficacy findings from clinical trials are generalisable to1137 patient populations treated in medical practice.1138 VII.B.5.18. PSUR section “Integrated benefit-risk analysis for authorised1139 indications”1140 The marketing authorisation holder should provide in this PSUR section an overall appraisal of the1141 benefit and risk of the medicinal product as used in clinical practice. Whereas sub-sections 16.41142 (“Characterisation of risks”) and 17.3 (“Characterisation of benefits”) present the risks and benefits,1143 this section should provide a critical analysis and integration of the key information in the previous1144 sections and should not simply duplicate the benefit and risk characterisation presented in the sub-1145 sections mentioned above.1146
  • 32. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 32/69 VII.B.5.18.1. PSUR sub-section “Benefit-risk context - medical need and important1147 alternatives”1148 This sub-section of the PSUR should provide a brief description of the medical need for the medicinal1149 product in the authorised indications and summarised alternatives (medical, surgical or other;1150 including no treatment).1151 VII.B.5.18.2. PSUR sub-section “Benefit-risk analysis evaluation”1152 A risk-benefit balance is specific to an indication and population. Therefore, for products authorised for1153 more than one indication, risk-benefit balancess should be evaluated and presented by each indication1154 individually. If there are important differences in the risk-benefit balance among populations within an1155 indication, the benefit-risk evaluation should be presented by population, if possible.1156 The benefit-risk evaluation should be presented and discussed in a way that facilitates the comparison1157 of benefits and risks and should take into account the following points :1158  Whereas previous sections/sub-sections should include all important benefit and risk information,1159 not all benefits and risks contribute importantly to the overall benefit-risk evaluation, therefore,1160 the key benefits and risks considered in the evaluation should be specified. The key information1161 presented in the previous benefit and risk section/sub-sections should be carried forward for1162 integration in the benefit-risk evaluation.1163  Consider the context of use of the medicinal product: the condition to be treated, prevented, or1164 diagnosed; its severity and seriousness; and the population to be treated (relatively healthy;1165 chronic illness, rare conditions).1166  With respect to the key benefit(s), consider its nature, clinical importance, duration, and1167 generalisability, as well as evidence of efficacy in non-responders to other therapies and alternative1168 treatments. Consider the effect size. If there are individual elements of benefit, consider all (e.g.1169 for therapies for rheumatoid arthritis: reduction of symptoms and inhibition of radiographic1170 progression of joint damage).1171  With respect to risk, consider its clinical importance, (e.g. nature of toxicity, seriousness,1172 frequency, predictability, preventability, reversibility, impact on patients), and whether it arose1173 from clinical trials in unauthorised indications or populations, off-label use, or misuse.1174  The strengths, weaknesses, and uncertainties of the evidence should be considered when1175 formulating the benefit-risk evaluation. Describe how uncertainties in the benefits and risks impact1176 the evaluation. Limitations of the assessment should be discussed.1177 Provide a clear explanation of the methodology and reasoning used to develop the benefit-risk1178 evaluation:1179  The assumptions, considerations, and judgement or weighting that support the conclusions of the1180 benefit-risk evaluation should be clear.1181  If a formal quantitative or semi-quantitative assessment of benefit-risk is provided, a summary of1182 the methods should be included.1183  Economic considerations (e.g. cost-effectiveness) should not be considered in the benefit-risk1184 evaluation.1185 When there is important new information or an ad hoc PSUR has been requested, a detailed benefit-1186 risk analysis should be presented based on cumulative data . Conversely, where little new information1187
  • 33. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 33/69 has become available during the reporting interval, the primary focus of the benefit-risk evaluation1188 might consist of an evaluation of updated interval safety data.1189 VII.B.5.19. PSUR section “Conclusions and actions”1190 A PSUR should conclude with the implications of any new information that arose during the reporting1191 interval in terms of the overall evaluation of benefit-risk for each authorised indication, as well as for1192 relevant subgroups, if appropriate.1193 Based on the evaluation of the cumulative safety data and the benefit-risk analysis, the marketing1194 authorisation holder should assess the need for changes to the reference product information and1195 propose changes as appropriate.1196 In addition and as applicable, the conclusions should include preliminary proposal(s) to optimise or1197 further evaluate the risk-benefit balance for further discussion with the relevant competent1198 authority(ies). This may include proposals for additional risk minimisation activities.1199 For products with a pharmacovigilance or risk management plan, the proposals should also be1200 considered for incorporation into the pharmacovigilance plan and/or risk minimisation plan, as1201 appropriate (see Module V).1202 Based on the evaluation of the cumulative safety data and the risk-benefit analysis, the marketing1203 authorisation holder shall draw conclusions in the PSUR as to the need for changes and/or actions,1204 including implications for the approved summary of product characteristics (SmPC) for the product(s)1205 for which the PSUR is submitted [IR Art 34(5)]. The regional appendix should include proposals for1206 product information (SmPC and package leaflet) together with information on ongoing changes when1207 applicable.1208 VII.B.5.20. Appendices to the PSUR1209 A PSUR should contain the following appendices as appropriate, numbered as follows:1210 1. Reference information(see VII.B.4.).1211 2. Cumulative summary tabulations of serious adverse events from clinical trials; and cumulative and1212 interval summary tabulations of serious and non-serious adverse reactions from post-marketing1213 data sources.1214 3. Tabular summary of safety signals (if not included in the body of the report)18 .1215 4. Listing of all the marketing authorisation holder-sponsored interventional and non-interventional1216 studies with the primary aim of identifying, characterising, or quantifying a safety hazard or1217 confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk1218 management measures, in case of non-interventional studies.1219 5. List of the sources of information used to prepare the PSUR (when desired by the marketing1220 authorisation holder).1221 6. Regional appendix:1222 The requirements for the regional appendix in the EU are provided in section VII.C.5..1223 1224 18 It is preferred to include the tabulation of signals in the body of the PSUR, if feasible.
  • 34. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 34/69 VII.B.5.21. Mapping signals and risks to PSUR sections/sub-sections1225 The following flowchart (Figure VII.1) reflects the general location for the presentation of information1226 on signals and risks within the PSUR.1227 Figure VII.1. PSUR Sections/subsections – signals and risks.1228 Key to benefit-risk evaluation? Safety data from available information sources Previously recognised risk? New information constituting a signal? Yes Safety signal detected? No No further documentation in the PSUR No Safety signal Section 15 Yes Close? Safety signal ongoing Section 15 Section 16.2 Yes Potential or Identified risk Important? Section 16.4 Yes Section 18.2 Yes Section 19 Consider update to E2E document, if applicable. Update RSI as appropriate No further documentation in the PSUR No Action(s) Proposed? No Yes Refuted signal No Section 16.3 New information on previously recognised identified/potential risk or missing information No No Yes 1229
  • 35. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 35/69 VII.B.6. Quality systems for PSURs at the level of marketing authorisation1230 holders1231 Marketing authorisation holders should have in place structures and processes for the preparation,1232 quality control, review and submission of PSURs including follow-up during and after their assessment.1233 These structures and processes should be described by means of written policies and procedures in the1234 marketing authorisation holder’s quality system (see Module I).1235 There are a number of areas in the pharmacovigilance process that can directly impact the quality of1236 PSURs, some examples are case management of spontaneous and study reports, literature screening,1237 signal management, additional pharmacovigilance and post-marketing research activities, procedures1238 for integration of information on benefits and risks from all available data sources and maintenance of1239 product information. The quality system should describe the links between the processes, the1240 communication channels and the responsibilities with the aim of gathering all the relevant information1241 for the production of PSURs. There should be documented procedures including quality control checks1242 in place to check the accuracy and completeness of the data presented in the PSURs. In ensuring1243 completeness of data, a documented template or plan for drawing data from various data sources1244 could be developed. The importance of an integrated approach to benefit-risk evaluation should1245 underpin processes and cross departmental input to PSUR preparation.1246 The PSUR should also contain the assessment of specific safety issues requested to be addressed in the1247 PSUR by competent authorities (worldwide). The marketing authorisation holder should have1248 mechanisms in place to ensure that the requests made by competent authorities (worldwide) during1249 the time of their PSUR assessment are properly addressed.1250 The provision of the data included in the summary tabulations (see VII.B.5.6.) should undergo source1251 data verification against the marketing authorisation holder’s safety database to ensure accuracy of the1252 number of events/reactions provided. The process for querying the safety database, the parameters1253 used for the retrieval of the data and the quality control performed should be properly documented.1254 An appropriate quality system should be in place in order to avoid failure to comply with PSUR1255 requirements such as:1256  non-submission: complete non-submission of PSURs, submission outside the correct submission1257 schedule or outside the correct time frames (without previous agreement with the competent1258 authorities);1259  unjustified omission of information required by VII.B.5.;1260  poor quality reports: poor documentation or insufficient information or evaluation provided to1261 perform a thorough assessment of the new safety information, signals, risk evaluation, benefit1262 evaluation and integrated benefit-risk analysis, misuse not highlighted, absence of use of1263 standardised medical terminology (e.g. MedDRA) and inappropriate dismissal of cases with no1264 reported risk factors in cumulative reviews;1265  submission of a PSUR where previous requests from competent authorities (worldwide) have not1266 been addressed.1267  failure to provide an explicit evaluation of the risk-benefit balance of the medicinal product;1268  failure to provide adequate proposals for the local authorised product information.1269 Any significant deviation from the procedures relating to the preparation or submission of PSURs1270 should be documented and the appropriate corrective and preventive action should be taken. This1271 documentation should be available at all times.1272
  • 36. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 36/69 When marketing authorisation holders are involved in contractual arrangements (e.g. licensor-1273 licensee), respective responsibilities for preparation and submission of the PSUR to the competent1274 authorities (worldwide) should be clearly specified in the written agreement.1275 When the preparation of the PSUR is delegated to third parties, the marketing authorisation holder1276 should ensure that they are subject to a quality system compliant with the current legislation. Explicit1277 procedures and detailed agreements should exist between the marketing authorisation holder and third1278 parties. The agreements may specifically detail the options to audit the PSUR preparation process.1279 VII.B.7. Training of staff members related to the PSUR process1280 For all organisations, it is the responsibility of the person responsible for the pharmacovigilance system1281 to ensure that the personnel, including pharmacovigilance, medical and quality personnel involved in1282 the preparation, review, quality control, submission and assessment of PSURs are adequately qualified,1283 experienced and trained according to the applicable guidelines (e.g. ICH E2C(R2) and this GVP Module1284 VII). When appropriate, specific training for the different processes, tasks and responsibilities relating1285 to the PSUR should be in place.1286 Training to update knowledge and skills should also take place as necessary.1287 Training should cover legislation, guidelines, scientific evaluation and written procedures related to the1288 PSUR process. Training records should demonstrate that the relevant training was delivered prior to1289 performing PSUR-related activities.1290 VII.C. Operation of the EU network1291 VII.C.1. PSUR process in the EU - General process1292 The following flowchart (Figure VII.2.) reflects the general process cycle for the PSUR procedure at the1293 EU level when recommendations by the PRAC are issued. This represents a high level cycle to outline1294 the entire process, from the preparation of the report to the implementation of the European1295 Commission decision/national actions when applicable. Different single steps in this flowchart are1296 formed by intermediate steps further explained and developed in different sections in this Module.1297
  • 37. Guideline on good pharmacovigilance practices (GVP) – Module VII EMA/252670/20122 Page 37/69 Figure VII.2. PSUR procedure - general process1298 1299 1300 MAH (10) PSUR creation EMA PSUR Repository PSUR 70/90 days PSUR PSUR available to Stakeholders NCAs, PRAC, CHMP, CMD(h), EC MA, EURD list, Standard PSUR submission schedule* PRAC Rapporteur or MS PSUR PRAC, CMDh Appointment of PRAC Rapporteur or MS EMA PSUR Repository 60 days PSUR PrAR available to Stakeholders NCAs, PRAC, CHMP, CMD(h), EC MAH (10) EMA PSUR Repository 30 days PRAC Rapporteur or MS 15 days PRAC CHMP PRAC Recommendation CMDh EMA PSUR Repository CHMP opinion CAP ± NAP If regulatory action is required NAPs Only If regulatory action is required DLP and frequency of Submission Comments PSUR PrAR PSUR PrAR EMA PSUR Repository PSUR updated AR Abbreviations used in this flowchart: MA: Marketing Authorisation MS: Member State EURD: European Union Reference Dates DLP: Data Lock Point MAH: Marketing Authorisation Holder NCA: National Competent Authorities CMD(h): Coordination Group for Mutual Recognition and Decentralised Procedures – Human PRAC: Pharmacovigilance and Risk Assessment Committee CHMP: Committee for Medicinal Products for Human use EC: European Commission PrAR: Preliminary Assessment Report AR: Assessment report CAP: Centrally authorised Product NAP: Nationally Authorised Product (including mutual recognition and decentralised procedure) *Standard PSUR submission schedule refers to 6 months, 1 year or 3 years as established in Directive 2001/83/EC Article 107C (2) 2nd paragraph. Next PRAC Meeting Legal references: 1 - [REG Art 28(2)] 2 - [DIR Art 107e(1)], [REG Art 28(3), 1st paragraph] 3 - [DIR Art 107e(2), 1st paragraph]. [REG Art 28(3), 2nd paragraph] 4 - [DIR Art 107e(2), 2nd paragraph], [REG Art 28(3), 3rd paragraph] 5 - [DIR Art 107e(3)], [REG Art 28(3), 4th paragraph] 6 - [DIR Art 107g(1) & (2), 1st paragraph)] 7 - [DIR Art 107g(3)], [REG Art 28(4)] 8 - [DIR Art 107g(4), [REG Art 28(4), 2nd paragraph & (5)] 9 - [DIR Art 107g(2), 3rd paragraph] 10 - [DIR Art 23(3)], [REG Art 16(3)] Repository: 1 - [REG Art 25a] 5 - [DIR Art 107e(3)], [REG Art 28(3), 4th paragraph] 3 4 5 6 7 8 9 PSUR updated AR EC EC No Agreement by consensus The MAH shall ensure that the product information is kept up to date with the current scientific knowledge, including the conclusions of the assessment and recommendations made public by means of the European medicines web-portal. 10 EC Decision CAPs National implementation NAPs only 2 National implementation Agreement by consensus CMDh Position MAH (10) MAH (10) MAH (10) 1301 1302 1303 1304 1305
  • 38. Guideline on good pharmacovigilance practices (GVP) – Module VII EMA/252670/20122 Page 38/69 VII.C.2. Standard submission schedule of PSURs1306 Marketing authorisation holders for products authorised before 02 July 2012 (centrally authorised1307 products) and 21 July 2012 (nationally authorised products) and for which the frequency and dates of1308 submission of PSURs are not laid down as a condition to the marketing authorisation or determined1309 otherwise in the list of Union reference dates shall submit PSURs according to the following submission1310 schedule (hereafter “standard” submission schedule) [REG 28(2), DIR Art 107c(2)]:1311  at 6 months intervals once the product is authorised, even if it is not marketed;1312  once a product is marketed, 6 monthly PSUR submission should be continued following initial1313 placing on the market in the EU for 2 years, then once a year for the following 2 years and1314 thereafter at 3-yearly intervals.1315 VII.C.3. List of European Union reference dates and frequency of1316 submission of PSURs19 1317 VII.C.3.1. Objectives of the EU reference dates list1318 The Agency shall make public a list of Union reference dates (hereinafter referred to as list of EU1319 reference dates) and frequency of submission of PSURs by means of the European medicines web-1320 portal [DIR Art 107c(7), REG Art 26(1)(g)].1321 The objectives of the list of EU reference dates and frequency of submission of PSURs are:1322  Harmonisation of data lock point and frequency of submission of PSURs for the same active1323 substance and combination of active substances:1324 For medicinal products containing the same active substance or combination of active substances1325 subject to different marketing authorisations, an EU reference date should be set up and the1326 frequency and date of submission of PSURs harmonised in order to allow the preparation of a1327 single assessment established in DIR Art 107e(1). Such information should be included in the list1328 published by the Agency.1329  Optimisation of the management of PSURs and PSURs assessments within the EU:1330 The list overrules the submission schedule described in DIR Art 107c(2)(b).1331 For active substances or combinations of active substances included in the list, marketing1332 authorisation holders shall vary, if applicable, the condition laid down in their marketing1333 authorisations in order to allow the submission of PSURs in accordance to the frequency and1334 submission date as indicated in the list [DIR 107c(4) to (7)].1335 The periodicity is defined on the basis of a risk-based approach in order to prioritise the periodic1336 re-evaluation of the risk-benefit balance of active substances in a way that best protects public1337 health. [Directive 2010/84/EU Preamble Recital 23].1338  Single EU assessment and reassessment of the risk-benefit balance of an active substance based1339 on all available safety data:1340 The list enables the harmonisation of PSUR submissions for medicinal products containing the1341 same active substance or the same combination of active substances.1342 19 The initial EU reference dates list was adopted by the CHMP/CMDh following consultation of the PRAC in September 2012 and was published on 01 October 2012.
  • 39. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 39/69 A single EU PSUR assessment provides a mechanism for evaluating the totality of available data on1343 the benefits and risks of an active substance or combination of active substances. The effective1344 application of work sharing principles is important in avoiding duplication of efforts and in1345 prioritising the use of limited resources in the best interests of European citizens.1346 VII.C.3.2. Description of the EU reference dates list1347 The Union reference date of medicinal products containing the same active substance or the same1348 combination of active substances shall be [DIR Art 107c(5)]:1349  the date of the first marketing authorisation in the EU of a medicinal product containing that active1350 substance or that combination of active substances; or1351  if the date of first marketing authorisation cannot be ascertained, the earliest of the known dates1352 of the marketing authorisations for a medicinal product containing that active substance or that1353 combination of active substances.1354 The list of EU reference dates and frequency of submission of PSURs consists of a comprehensive list of1355 substances and combinations of active substances in alphabetical order, for which PSURs, where1356 required, shall be submitted in accordance with the EU reference date and the frequency as1357 determined by the Committee for Medicinal Products for Human Use (CHMP) and the Coordination1358 Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) following consultation1359 with the Pharmacovigilance and Risk Assessment Committee (PRAC) [DIR Art 107c(4) and (6)]. The1360 list should be updated in line with the “list of all medicinal products for human use authorised in the1361 Union” as referred to in REG Art 57(1)(b).1362 The EU reference dates list should contain the following information:1363  the EU reference dates;1364  the frequencies of submission of PSURs;1365  the data lock points of the next submissions of PSURs;1366  the date of publication (on the European Medicines web-portal) of the frequency for PSURs1367 submission and data lock point for each active substance and combination of active substances.1368 Any change to the dates of submission and frequency on PSURs specified in the marketing1369 authorisation shall take effect 6 months after the date of such publication [DIR Art 107c(7)]1370 Where specificity is deemed necessary, the list should include the scope of the PSUR and related EU1371 single assessment procedure (see VII.C.3.3.) such as:1372  whether or not it should cover all the indications of the substance or combination of active1373 substances;1374  whether or not it should cover all the formulations/routes of administration of the products1375 containing a substance or combination of active substances;1376  whether generic, well-established use, traditional herbal and homeopathic medicinal products shall1377 submit a PSUR due to a request from a competent authority or due to concerns relating to1378 pharmacovigilance data or due to the lack of PSURs relating to an active substance after the1379 marketing authorisation has been granted [DIR Art 107c(2) second subparagraph] (see1380 VII.C.3.3.2.).1381 1382
  • 40. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 40/69 VII.C.3.3. Application of the list of EU reference dates to submission of1383 PSURs1384 VII.C.3.3.1. Submission of PSURs for medicinal products: general requirement1385 Figure VII.3. presents the various potential scenarios for the submission of a PSUR as a general1386 requirement.1387 Figure VII.3. Conditions for PSURs submission as general requirement1388 1389 Medicinal product Does the marketing authorisation include a condition on the frequency of PSURs submission? Is the substance or combination included in the EURD list? No Follow the frequency as indicated in DIR Art 107c(2) until a frequency is laid down in the marketing authorisation or the substance (or combination) is included in the EURD list No Is the substance or combination included in the EURD list? Yes Follow the frequency as laid down in the marketing authorisation No If applicable, variation of the marketing authorisation to update the frequency as published in the EURD list Yes Follow the frequency as indicated in the EURD list Yes 1390
  • 41. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 41/69 The data lock points included in the list of EU references dates enable the synchronisation of PSURs1391 submission for products subject to different marketing authorisations and permit the EU single1392 assessment. These data lock points are fixed on a certain date of the month, and should be used to1393 determine the submission date (which has legal status) of the PSUR. Marketing authorisation holders1394 can request to amend those dates in accordance with section VII.C.3.5.2.1395 Unless otherwise specified in the list of EU reference dates and frequency of submission, or agreed with1396 competent authorities in Member States or the Agency, as appropriate, a single PSUR shall be1397 prepared for all medicinal products containing the same active substance and authorised for one1398 marketing authorisation holder. The PSUR shall cover all indications, routes of administration, dosage1399 forms and dosing regimens, irrespective of whether authorised under different names and through1400 separate procedures. Where relevant, data relating to a particular indication, dosage form, route of1401 administration or dosing regimen shall be presented in a separate section of the PSUR and any safety1402 concerns shall be addressed accordingly [IR Art 34(6)].1403 For medicinal products containing an active substance or a combination of active substances not1404 included in the EU reference dates list, PSURs shall be submitted according to the PSUR frequency1405 defined in the marketing authorisation or if not specified, in accordance with the submission schedule1406 specified in DIR Art 107c(2) and REG Art 28(2).1407 VII.C.3.3.2. Submission of PSURs for generic, well-established use, traditional herbal and1408 homeopathic medicinal products1409 By way of derogation, generics (authorised under DIR Art 10(1)), well-established use (authorised1410 under DIR Art 10a), homeopathic (authorised under DIR Art 14) and traditional herbal (authorised1411 under DIR Art 16a) medicinal products are exempted from submitting PSURs except in the following1412 circumstances [DIR Art 107b(3)]:1413  the marketing authorisation provides for the submission of PSURs as a condition;1414  PSURs is (are) requested by a competent authority in a Member State on the basis of concerns1415 relating to pharmacovigilance data or due to the lack of PSURs relating to an active substance after1416 the marketing authorisation has been granted (e.g. when the “reference” medicinal product is no1417 longer marketed). The assessment reports of the requested PSURs shall be communicated to the1418 PRAC, which shall consider whether there is a need for a single assessment report for all marketing1419 authorisations for medicinal products containing the same active substance and inform the CMDh1420 or CHMP accordingly, in order to apply the procedures laid down in DIR Art 107c(4) and 107e.1421 In order to facilitate and optimise the PSUR EU single assessment process, to avoid duplications of1422 requests for PSURs and to provide transparency and predictability for the marketing authorisation1423 holders, the legislative provision laid down in DIR 107b(3)(b) is applied by specifying in the list of EU1424 reference dates, the substances for which PSURs for generic, well-established use, traditional herbal1425 and homeopathic medicinal products are required. This specification is based on the request made by a1426 competent authority in a Member State during the creation or maintenance of the list of EU reference1427 dates and on the basis of concerns relating to pharmacovigilance data or due to the lack of PSURs1428 relating to an active substance.1429 The harmonised frequency for the submission of the reports and the EU reference dates are1430 determined by the CHMP and/or CMDh after consultation of the PRAC.1431 The application of the list of EU reference dates for the submission of PSURs for generic, well-1432 established use, traditional herbal and homeopathic medicinal products does not undermine the right1433 of a competent authority in a Member State to request the submission of PSURs at any time under the1434 provision laid down in [DIR Art 107c(2) second subparagraph].1435
  • 42. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 42/69 For products where PSURs are no longer required to be submitted routinely, it is expected that1436 marketing authorisation holders will continue to evaluate the safety of their products on a regular basis1437 and report any new safety information that impacts on the risk-benefit balance or the product1438 information (See Module VI and Module IX).1439 Figure VII.4. presents the various potential scenarios as regard the submission of a PSUR for generic,1440 well-established use, traditional herbal and homeopathic medicinal products:1441 Figure VII.4. Conditions for PSURs submission for generic, well-established use, traditional herbal1442 and homeopathic medicinal products1443 1444 Medicinal product Does the marketing authorisation include a condition on the frequency of PSURs submission? Is the substance or combination included in the EURD list? No No PSUR is required No Is the substance or combination included in the EURD list? Yes Follow the frequency as laid down in the marketing authorisation No If applicable, variation of the marketing authorisation to update the frequency as published in the EURD list Follow the frequency as indicated in the EURD list Are PSURs requested for generics, well-established use, traditional herbals or homeopathic?* Yes Are PSURs requested for generics, well-established use, traditional herbals or homeopathic?* Yes No Yes Yes No * Whether marketing authorisation holders for generics, well-established use, traditional herbal and homeopathic medicinal products are requested to submit PSURs following a request of a competent authority in a Member State due to concerns relating to pharmacovigilance data or lack of PSUR submission. 1445
  • 43. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 43/69 VII.C.3.3.3. Submission of PSURs for fixed dose combination products1446 Unless otherwise specified in the list of EU reference dates and frequency of submission, if the1447 substance that is the subject of the PSUR is also authorised as a component of a fixed combination1448 medicinal product, the marketing authorisation holder shall either submit a separate PSUR for the1449 combination of active substances authorised for the same marketing authorisation holder with cross-1450 references to the single-substance PSUR(s), or provide the combination data within one of the single-1451 substance PSURs [IR Art 34(7)].1452 VII.C.3.3.4. Submission of PSURs on demand of a competent authority in a Member State1453 Marketing authorisation holders shall submit PSURs immediately upon request from a competent1454 authority in a Member State [DIR Art 107c(2)]. To facilitate the EU assessment and avoid duplication1455 requests, the competent authorities in the Member States should normally make use of the list of EU1456 reference dates to request the submission of PSURs, however in especial circumstances competent1457 authorities in Member States can directly request the submission of a PSUR. When the timeline for1458 submission has not been specified in the request, marketing authorisation holders should submit the1459 PSUR within 90 calendar days of the data lock point.1460 VII.C.3.4. Criteria used for defining the frequency of submission of PSURs1461 When deviating from the PSUR submission schedule defined in DIR Art 107c(2)(b), the frequencies of1462 submission of PSURs and the corresponding data lock points should be defined on a risk-based1463 approach by the CHMP where at least one of the marketing authorisations concerned has been granted1464 in accordance with the centralised procedure or by the CMDh otherwise, after consultation with the1465 PRAC.1466 The following prioritisation criteria should be taken into account when defining the frequency of1467 submission for a given active substance or combination of active substances:1468  information on risks or benefits that may have an impact on the public health;1469  new product for which there is limited safety information available to date (includes pre- and post-1470 authorisation experiences);1471  significant changes to the product (e.g. new indication has been authorised, new pharmaceutical1472 form or route of administration broadening the exposed patient population);1473  vulnerable patient populations/poorly studied patient populations, important missing information1474 (e.g. children, pregnant women) while these populations are likely to be exposed in the post-1475 authorisation setting;1476  signal of/potential for misuse, medication error, risk of overdose or dependency;1477  the size of the safety database and exposure to the medicinal product;1478  medicinal products subjected to additional monitoring.1479 Any change in the criteria listed above for a given active substance or combination of active substances1480 may lead to an amendment of the list of EU reference dates (e.g. increase of the frequency for PSUR1481 submission).1482
  • 44. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 44/69 VII.C.3.5. Maintenance of the list of EU reference dates1483 VII.C.3.5.1. General principles1484 The maintenance of the list of EU reference dates should facilitate regulatory responsiveness to public1485 health concerns identified within the EU and therefore the list will be subject to changes to reflect the1486 decisions taken (e.g. by the Agency’s committees following signal detection).1487 The information included in the list such as the active substances and combinations of active1488 substances, the frequencies of submission of PSURs and data lock points may need to be updated1489 when considered necessary by the CHMP or CMDh after consultation with the PRAC. Changes to the list1490 may be applied on one of the following grounds:1491  emergence of new information that might have an impact on the risk-benefit balance of the active1492 substances or combinations of active substances, and potentially on public health;1493  any change in the criteria used for the allocation of frequency for PSUR submission and defined1494 under VII.C.3.4.;1495  a request from the marketing authorisation holders as defined under DIR Art 107c(6);1496  active substance newly authorised.1497 Figure VII.5. provides a general overview of the maintenance of the list of EU reference dates and1498 frequency of submission of PSURs1499
  • 45. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 45/69 Figure VII.5. Maintenance of the list of EU reference dates and frequency of submission of PSUR1500 1501 Request for national competent authorities or marketing authorisation holders to determine the EU reference date or to change the frequency of PSURs submission Emergence of new safety information or change in the criteria used for the allocation of frequency of PSURs submission New Centrally Authorised product containing an active substance not included in the EURD list or included with a different frequency of PSURs submission CHMP/CMDh Scientific review and consideration by the PRAC For consultation PRAC recommendation on the amendment of the EURD list CHMP opinion/CMDh position Need to amend the EURD list? End No Publication of the amended EURD list in the European medicines web-portal Yes Where appropriate, marketing authorisation holders shall submit a variation to reflect the changes in their marketing authorisations 1502 1503
  • 46. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 46/69 VII.C.3.5.2. Requests from marketing authorisation holders to amend the list of EU1504 reference dates1505 Marketing authorisation holders shall be allowed to submit a request to the CHMP or the CMDh, as1506 appropriate, to determine the Union reference dates or to change the frequency of submission of PSUR1507 on one of the following grounds [DIR Art 107c(6)]:1508  for reasons relating to public health;1509  in order to avoid a duplication of the assessment;1510  in order to achieve international harmonisation.1511 The request and its grounds should be considered by the PRAC and the CHMP if it concerns at least one1512 marketing authorisation granted in accordance with the centralised procedure or the CMDh otherwise,1513 which will either approve or deny the request.1514 The list will then be amended accordingly when appropriate and published on the European medicines1515 web-portal (see section VII.C.3.6.).1516 For details about how to submit requests for amendments to the list, refer to the EU reference dates1517 cover note and the related template published on the European medicines web-portal20 1518 VII.C.3.6. Publication of the list1519 Upon its establishment and adoption by the CHMP and CMDh following PRAC consultation, the list of EU1520 reference dates and frequency of submission of PSURs is published on the European medicines web-1521 portal.1522 In case of amendments, the updated list should be published following its adoption by the CHMP or the1523 CMDh. It is expected to be updated monthly.1524 VII.C.3.7. Amendment of the marketing authorisation according to the list1525 of EU reference dates1526 Any changes to the dates and frequencies of submission of PSURs specified in the list take effect six1527 months after the date of the publication on the European medicines web-portal Where appropriate,1528 marketing authorisation holders shall submit the relevant variation in order to reflect the changes in1529 their marketing authorisation [DIR 107c(6)], unless the marketing authorisation contains a direct cross1530 reference to the list of EU references dates. Where appropriate, marketing authorisation holders shall1531 submit the relevant variation in order to reflect the new information in their marketing authorisations1532 [DIR 107c(6)].1533 VII.C.4. Processes for PSUR Assessment in the EU network1534 The competent authorities in the Member States shall assess PSURs to determine whether there are1535 new risks or whether risks have changed or whether there are changes to the risk-benefit balance of1536 the medicinal product [DIR Art 107d].1537 For purely nationally authorised medicinal products authorised in one Member State, the assessment of1538 PSURs is conducted by the competent authority in the Member State where the product is authorised1539 (see VII.C.4.1.).1540 20 http://www.emea.europa.eu
  • 47. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 47/69 For medicinal products authorised in more than one Member State (i.e. centrally authorised products,1541 products authorised through the mutual recognition and decentralised procedures) and for medicinal1542 products subject to different national marketing authorisations containing the same active substance or1543 the same combination of active substances whether or not held by the same marketing authorisation1544 holders and for which the frequency and dates of submission of PSURs have been harmonised in the1545 list of EU reference dates, an EU single assessment of all PSURs is conducted with recommendation1546 from the PRAC in accordance with the procedure described in VII.C.4.2.1. and VII.C.4.2.2..1547 Further to assessment of the PSUR and opinion from the CHMP or position from the CMDh, as1548 applicable, following the recommendation from the PRAC, the competent authorities in Member States,1549 or the European Commission for centrally authorised products, shall take the necessary measures to1550 vary, suspend or revoke the marketing authorisation(s), in accordance with outcome of the1551 assessment [DIR Art 107g(2)] [REG Art 28(4) and (5)] (see VII.C.4.2.3. and VII.C.4.2.4.).1552 The outcome of the PSUR assessment results in a legally binding decision or position in case of any1553 action to vary, suspend, revoke the marketing authorisations of the medicinal products containing the1554 concerned active substance or combination of active substances, on the basis of the position of the1555 CMDh or the opinion of the CHMP following the recommendations from the PRAC. Furthermore,1556 marketing authorisation holders are reminded of their obligation to keep their marketing authorisation1557 up to date in accordance with REG Art 16(3) and DIR Art 23(3). The recommendations are therefore1558 implemented in a harmonised and timely manner for all products within the scope of the procedure1559 across the EU.1560 Amendments to the SmPC, package leaflet and labelling as a result of the PSUR assessment should be1561 implemented without subsequent variation submission for centrally authorised products and through1562 the appropriate variation for nationally authorised products, including those authorised through the1563 mutual recognition and decentralised procedures.1564 When the proposals for the product information include new adverse reactions in section 4.81565 (“Undesirable effects”) of the SmPC, or modifications in the description, frequency and severity of the1566 existing reactions, marketing authorisation holders should provide in the PSUR detailed information to1567 allow the adequate description and classification of the frequency of the adverse reactions. If other1568 sections of the SmPC (e.g. SmPC section 4.4 “Special warnings and precautions for use”) are1569 considered to be updated, clear proposals should be provided for the competent authorities in the1570 Member States to consider during the PSUR assessment21 . The proposals should be included in the1571 PSUR regional appendix (VII.C.5.).1572 Harmonisation of the entire product information in all the Member States where the product is1573 authorised is not one of the objectives of the PSUR assessment procedure. Instead, the outcome of the1574 assessment should incorporate the new safety warnings and key risk minimisation recommendations,1575 arising from the assessment of the data in the PSUR, to be included in the relevant sections of the1576 product information.1577 VII.C.4.1. PSURs for purely nationally authorised medicinal products1578 It is the responsibility of the competent authority in the Member State where the product is authorised1579 to evaluate the PSURs for these medicinal products and the assessment is conducted in accordance1580 with the national legislation.1581 Listings of individual cases may be requested in the context of the PSUR assessment procedure for1582 adverse reactions of special interest and should be provided by the marketing authorisation holder1583 21 See “Guideline on Summary of Product Characteristics” as published on the Website of the European Commission in the Notice to Applicants, Volume 2C: http://ec.europa.eu/health/files/eudralex
  • 48. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 48/69 within an established timeframe to be included in the request. This may be accompanied by a request1584 for an analysis of cases classified as non-serious.1585 Following the assessment of PSURs, the competent authority in the Member State should consider1586 whether any action concerning the marketing authorisation for the medicinal product concerned is1587 necessary. They should vary, suspend or revoke the marketing authorisation when applicable1588 according to the appropriate procedure at national level.1589 The assessment report and conclusions of the competent authority in the Member State should be1590 provided to the marketing authorisation holder.1591 VII.C.4.2. Medicinal products authorised in more than one Member State1592 VII.C.4.2.1. Assessment of PSURs for a single centrally authorised medicinal product1593 This section describes the assessment of PSURs where only one centrally authorised medicinal product1594 is involved according to the procedure set up in Article 28 of Regulation (EC) No 726/2004 (see figure1595 VII.6.).1596
  • 49. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 49/69 Figure VII.6. PSUR assessment procedure for a single centrally authorised medicinal product1597 Receipt of PSUR(s) from MAH(s) Technical validation by the Agency Start Rapporteur preliminary assessment report 60 days Comments from MAH(s) and members of the PRAC 30 days Rapporteur updated assessment report 15 days PRAC recommendation At the next PRAC meeting PRAC recommendation received by CHMP If variation, suspension or revocation of the marketing authorisation is recommended CHMP opinion with timetable for implementation 30 days Opinion sent to EC, marketing authorisation holder and NCAs EC decision to update centralised marketing authorisation 1598
  • 50. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 50/69 The assessment of PSURs for a single centrally authorised medicinal product is coordinated by the1599 Agency and shall be conducted by a Rapporteur appointed by the PRAC [REG Art 28(3)] (hereinafter1600 referred to as “PRAC Rapporteur”).1601 Upon receipt, the Agency should perform a technical validation of the report to ensure that the PSUR1602 application is in a suitable format.1603 Listings of individual cases from EudraVigilance database may be retrieved to support the PSUR1604 assessment.1605 Further to the above verifications, the Agency acknowledges receipt of the report and starts the1606 procedure in accordance with the official starting dates published on the Agency's website. The1607 submission deadlines and detailed procedural timetables are published as a generic calendar on the1608 Agency's website.1609 The published timetables identify the submission, start and finish dates of the procedures as well as1610 other interim dates/milestones that occur during the procedure.1611 During the assessment, additional listings of individual cases may be requested by the PRAC1612 Rapporteur through the Agency, for adverse reactions of special interest and should be provided by the1613 marketing authorisation holder(s) within an established timeframe to be included in the request. This1614 may be accompanied by a request for an analysis of cases classified as non-serious.1615 During the drafting of the assessment report, the PRAC Rapporteur shall closely collaborate with the1616 CHMP Rapporteur [REG Art 28(3)].1617 The PRAC Rapporteur shall prepare an assessment report and send it to the Agency and to the1618 members of the PRAC [REG Art 28(3)] within 60 days of the start of the procedure.1619 The Agency shall send the PRAC Rapporteur’s preliminary assessment report to the marketing1620 authorisation holder [REG Art 28(3)].1621 By Day 90, the marketing authorisation holder and members of the PRAC may send comments on the1622 PRAC Rapporteur’s preliminary assessment report to the Agency and the PRAC Rapporteur. Those1623 comments should also include responses to outstanding issues or questions raised by the PRAC1624 Rapporteur in the preliminary assessment report and which can be addressed within the timeframe of1625 the comments phase.1626 Following receipt of comments, the PRAC Rapporteur shall prepare an updated assessment report [REG1627 Art 28(3)] within 15 days (i.e. by Day 105). The updated assessment report is made available to the1628 members of the PRAC.1629 An oral explanation to the PRAC can be held at the request of the PRAC or the marketing authorisation1630 holder in case of recommendation for a revocation or suspension of the marketing authorisation, a new1631 contraindication, a restriction of the indication or a reduction of the recommended dose.1632 The PRAC shall adopt the updated assessment report with or without further changes at its next1633 meeting [REG Art 28(3)], together with a recommendation on the maintenance of the marketing1634 authorisation or the need to vary, suspend or revoke the marketing authorisation. The PRAC1635 recommendation may also highlight the need to conduct a post-authorisation safety study, request an1636 update of the RMP, review of safety issues and/or close monitoring of events of interest.1637 Divergent positions of PRAC members and the grounds on which they are based shall be reflected in1638 the recommendation issued by the PRAC [REG Art 28(3)].1639 The Agency shall include the PRAC recommendation and adopted assessment report in the repository,1640 and forward both to the marketing authorisation holder [REG Art 28(3)].1641
  • 51. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 51/69 Further to adoption at the PRAC meeting, in case of any regulatory action is recommended, the1642 assessment report and PRAC recommendation are sent to the CHMP for adoption of an opinion for the1643 centrally authorised product concerned as described in VII.C.4.2.3..1644 VII.C.4.2.2. Assessment of PSURs for medicinal products subject to different marketing1645 authorisations containing the same active substance (EU single assessment)1646 This section describes the assessment of PSURs for medicinal products subject to different marketing1647 authorisations containing the same active substance or the same combination of active substances1648 whether or not held by the same marketing authorisation holder and for which the frequency and dates1649 of submission of PSUR have been harmonised in the list of EU reference dates. This could include a1650 mixture of centrally authorised products, products authorised through the mutual recognition and1651 decentralised procedures and purely nationally authorised products [DIR Art 107e to 107g] (so-called1652 PSUR “EU single assessment” procedure).1653
  • 52. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 52/69 Figure VII.7. PSUR assessment procedure for “EU single assessment”1654 Receipt of PSUR(s) from MAH(s) Technical validation by the Agency Start Rapporteur/MS preliminary assessment report 60 days Comments from MAH(s) and NCAs 30 days Rapporteur/MS updated assessment report 15 days PRAC recommendation At the next PRAC meeting Is variation, suspension or revocation of the marketing authorisation is recommended PRAC recommendation sent to MAH(s) No CAP included? Yes PRAC recommendation received by CMDh No CMDh position with timetable for implementation Majority position sent to EC, MAH(s) and NCAs Agreed position sent to MAH(s) and NCAs Implementation at national level according to the appropriate procedure EC decision to NCAs on measures to be taken Implementation at national level according to the appropriate procedure PRAC recommendation received by CHMP CHMP opinion with timetable for implementation 30 days Opinion sent to EC, MAH(s) and NCA EC decision to update centralised MA EC decision to NCAs on measures to be taken Implementation at national level according to the appropriate procedure 30 days By majorityBy consensus Yes For CAPs For Non-Caps 1655
  • 53. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 53/69 The assessment of PSURs for medicinal products, also called “EU single assessment”, shall be1656 conducted by [DIR Art 107e(1)]:1657  a “Member State” appointed by the CMDh where none of the marketing authorisations concerned1658 has been granted in accordance with the centralised procedure;1659  a “Rapporteur” appointed by the PRAC, where at least one of the marketing authorisations1660 concerned has been granted in accordance with the centralised procedure (hereinafter referred to1661 as “PRAC Rapporteur”).1662 The PSUR EU single assessment procedure is coordinated by the Agency. Upon receipt, the Agency1663 should perform a technical validation of the reports to ensure that the PSURs applications are in a1664 suitable format.1665 Upon establishment of the list of all medicinal products for human use authorised in the EU referred to1666 in REG Art 57, the Agency should ensure that all marketing authorisation holder(s) of the given1667 substance have submitted PSUR(s), as required. In the event where a PSUR has not been submitted,1668 the Agency should contact the concerned marketing authorisation holder(s). However, this will not1669 preclude the start of the single assessment procedure for other PSUR(s) of the same active substance.1670 Listings of individual cases from EudraVigilance database may be retrieved to support the PSURs1671 assessment.1672 Further to the above verifications, the Agency acknowledges receipt of the report(s) and starts the1673 procedure in accordance with the official starting dates published on the Agency's website. The1674 submission deadlines and full procedural detailed timetables are published as a generic calendar on the1675 Agency's website.1676 The published timetables identify the submission, start and finish dates of the procedures as well as1677 other interim dates/milestones that occur during the procedure.1678 Further to the start of procedure, the PRAC Rapporteur or Member State conducts the single1679 assessment of all PSURs submitted for the given active substance.1680 During the assessment, additional listings of individual cases may be requested by the PRAC1681 Rapporteur or Member State through the Agency for adverse drug reactions of special interest and1682 should be provided by the marketing authorisation holder(s) within an established timeframe to be1683 included in the request. This may be accompanied by a request for an analysis of cases classified as1684 non-serious.1685 The PRAC Rapporteur or Member State shall prepare an assessment report and send it to the Agency1686 and to the Member States concerned [DIR Art 107e(2)] within 60 days of the start of the procedure.1687 This preliminary assessment report should be circulated to the members of the PRAC.1688 The Agency shall send the PRAC Rapporteur’s/Member State preliminary assessment report to the1689 concerned marketing authorisation holder(s) [DIR Art 107e(2)].1690 By Day 90, the marketing authorisation holder(s), Member States and members of the PRAC as1691 applicable may send comments on the PRAC Rapporteur’s/Member State’s preliminary assessment1692 report to the Agency and the PRAC Rapporteur/Member State, as applicable. Those comments should1693 also include responses to outstanding issues or questions raised by the PRAC Rapporteur/Member1694 State in the preliminary assessment report and which can be addressed within the timeframe of the1695 comments phase.1696 1697
  • 54. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 54/69 Following receipt of comments, the PRAC Rapporteur/Member State shall prepare an updated1698 assessment report [DIR Art 107e (3)] within 15 days (i.e. by Day 105). The updated assessment1699 report is forwarded to the members of the PRAC.1700 An oral explanation to the PRAC can be held at the request of the PRAC or the marketing authorisation1701 holder in case of recommendation for a revocation or suspension of the marketing authorisation, a new1702 contraindication, a restriction of the indication or a reduction of the recommended dose.1703 The PRAC shall adopt the updated assessment report with or without further changes at its next1704 meeting [DIR Art 107e(3)], together with a recommendation on maintenance of the marketing1705 authorisation or the need to vary, suspend or revoke the marketing authorisation. The PRAC1706 recommendation may also highlight the need to conduct a post-authorisation safety study (see Module1707 VIII), request an update of the RMP (see Module V), review of safety issue and/or close monitoring of1708 events of interest.1709 Divergent positions of PRAC members and the grounds on which they are based shall be reflected in1710 the recommendation issued by the PRAC [DIR Art 107e(3)].1711 The Agency shall include the PRAC recommendation and adopted assessment report in the repository,1712 and forward both to the marketing authorisation holder(s) [DIR Art 107e(3)].1713 Further to adoption at the PRAC meeting, in case of any regulatory action is recommended, the1714 assessment report and PRAC recommendation are sent to:1715  the CHMP where at least one centrally authorised product is included in the single assessment, for1716 adoption of an opinion as described in VII.C.4.2.3.;1717  the CMDh where no centrally authorised product is included in the single assessment, for1718 agreement of a position as described in VII.C.4.2.4..1719 VII.C.4.2.3. Single assessment including at least one centrally authorised product leading to1720 a CHMP opinion1721 The CHMP acknowledges receipt of the PRAC recommendation and assessment report, in case of any1722 regulatory action, at their next meeting following the PRAC adoption. Within 30 days from receipt, the1723 CHMP shall consider the PRAC assessment report and recommendation and adopt an opinion on the1724 maintenance, variation, suspension, revocation of the marketing authorisation(s) concerned [DIR1725 107g(3)].1726 An oral explanation to the CHMP can be held at the request of the CHMP or the marketing authorisation1727 holder(s) only in case of differences with the PRAC recommendation where CHMP considers the1728 possibility of adopting an opinion on the suspension or revocation of the marketing authorisation(s), a1729 new contraindication, a restriction of the indication or a reduction of the recommended dose.1730 The opinion will contain the following:1731  the final assessment report and recommendation adopted by the PRAC;1732  detailed explanation of the scientific grounds for differences with the PRAC recommendation, if1733 applicable [DIR Art 107g(3)];1734  in the case of a CHMP opinion to vary the marketing authorisation(s):1735  the scientific conclusions and grounds recommending the variation to the terms of the1736 marketing authorisation;1737
  • 55. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 55/69  for centrally authorised products, revised product information and if applicable, conditions1738 imposed to the marketing authorisation holder and where appropriate, the conditions or1739 restrictions imposed to the Member States for the safe and effective used of the medicinal1740 product, in accordance with the provision provided in DIR Art 127a;1741  for nationally authorised products, including those authorised through the mutual recognition1742 and decentralised procedures, an annex indicating the new safety warnings and key risk1743 minimisation recommendations to be included in the relevant sections of the product1744 information as applicable.1745  in the case of a CHMP opinion to suspend the marketing authorisation(s), the scientific conclusions1746 together with the grounds for suspension and conditions for lifting the suspension;1747  in the case of a CHMP opinion to revoke the marketing authorisation(s), the scientific conclusions1748 together with the grounds for revocation;1749  divergent positions of CHMP members, where applicable.1750 Further to adoption, the Agency should send the CHMP opinion together with its annexes and1751 appendices to the European Commission, marketing authorisation holder(s) and competent authorities1752 in Member States.1753 The final assessment conclusions and recommendations are published in the European medicines web-1754 portal (VII.C.7.).1755 a. Post CHMP opinion - Centrally authorised products1756 Where the CHMP opinion states that the terms of the marketing authorisation(s) needs to be varied,1757 the marketing authorisation holder(s) of centrally authorised products should provide the translations1758 of the product information in all EU official languages, in accordance with the translation timetable1759 adopted by the CHMP.1760 Further to receipt of a CHMP opinion stating that regulatory action to the concerned marketing1761 authorisation is necessary, the European Commission shall adopt a decision addressed to marketing1762 authorisation holders to vary, suspend or revoke the marketing authorisation(s) of centrally authorised1763 product(s) [DIR Art 107g(4b)].1764 Further to adoption, the European Commission should notify the decisions amending the terms of the1765 marketing authorisation of centrally authorised products to the marketing authorisation holder(s).1766 b. Post CHMP opinion - Nationally authorised products, including those authorised through1767 the mutual recognition and decentralised procedures1768 Further to receipt of a CHMP opinion stating that regulatory action to the concerned marketing1769 authorisations is necessary, the European Commission shall adopt a decision addressed to the1770 competent authorities in Member States concerning the measures to be taken [DIR Art 107g(a)] in1771 respect of nationally authorised products, including those authorised through the mutual recognition1772 and decentralised procedures.1773 Further to the receipt of the decision from the European Commission, the competent authorities in1774 Member States shall take the necessary measures to vary, suspend or revoke the marketing1775 authorisation(s) within 30 days [DIR Art 107g(4)].1776
  • 56. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 56/69 VII.C.4.2.4. Single assessment not including centrally authorised product leading to a CMDh1777 position1778 The CMDh acknowledges receipt of the PRAC recommendation and assessment report, in case of any1779 regulatory action, at their next meeting following the PRAC adoption.1780 Within 30 days from receipt, the CMDh shall consider the PRAC assessment report and1781 recommendation and reach a position on the maintenance, variation, suspension, revocation of the1782 marketing authorisation(s) concerned [DIR Art 107g(1)].1783 An oral explanation to the CMDh can be held at the request of the CMDh or the marketing1784 authorisation holder(s), only in case of differences with the PRAC recommendation where the CMDh1785 considers the possibility to reach a position on the suspension or revocation of the marketing1786 authorisation(s), a new contraindication, a restriction of the indication or a reduction of the1787 recommended dose.1788 The position will contain the following:1789  the final assessment report and recommendation adopted by the PRAC;1790  detailed explanation of the scientific grounds for differences with the PRAC recommendation, if1791 applicable [DIR Art 107g(2)];1792  in the case of a CMDh position to vary the marketing authorisation(s), the scientific conclusions1793 and grounds recommending the variation to the terms of the marketing authorisation and an1794 annex indicating the new safety warnings and key risk minimisation recommendations to be1795 included in the relevant sections of the product information, as applicable;1796  in the case of a CMDh position to suspend the marketing authorisation(s), the scientific conclusions1797 together with the grounds for suspension and conditions for lifting the suspension;1798  in the case of a CMDh position to revoke the marketing authorisation(s), the scientific conclusions1799 together with the grounds for revocation;1800  divergent position(s) for the CMDh members, where applicable.1801 The final assessment conclusions and recommendations shall be published by the Agency in the1802 European medicines web-portal [DIR Art 107l] (VII.C.7.).1803 If the CMDh position is reached by consensus:1804 The position agreed including the action to be taken is recorded by the chairperson in the minutes of1805 the CMDh meeting where agreed.1806 The chairman shall send the agreed CMDh position [DIR Art 107g(2)] and its appendices to the1807 marketing authorisation holder(s) and competent authorities in Member States.1808 Further to receipt of the CMDh position stating that regulatory action to the concerned marketing1809 authorisation is necessary, the competent authorities in Member States shall adopt necessary1810 measures to vary, suspend or revoke the marketing authorisation(s) concerned in accordance with the1811 timetable for implementation determined in the agreed position [DIR Art 107g(2)].1812 In case the position of the CMDh agreed that variation to the terms of marketing authorisation is1813 required, the marketing authorisation holder(s) shall submit the relevant variation to that effect within1814 the timetable for implementation [DIR Art 107g(2)] as appended to the agreed position.1815 If the CMDh position is reached by majority vote:1816
  • 57. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 57/69 The majority position on the action to be taken is recorded by the chairman in the minutes of the1817 CMDh meeting where agreed.1818 The majority position of the CMDh together with its annexes and its appendices, including translations1819 in all EU official languages where applicable, shall be forwarded to the European Commission [DIR Art1820 107g(2)]. The position of the CMDh should also be forwarded to the competent authorities in Member1821 States.1822 Further to receipt of a CMDh position stating that regulatory action to the concerned marketing1823 authorisation is necessary, the European Commission shall adopt decision(s) [DIR Art 107g(2)]1824 addressed to the competent authorities in Member States in order for them to vary, suspend or revoke1825 the marketing authorisation(s) of nationally authorised product(s) which is addressed to marketing1826 authorisation holders.1827 Further to receipt of the decision from the European Commission, the competent authorities in Member1828 States shall take the necessary measures to maintain, vary, suspend or revoke the marketing1829 authorisation(s) within 30 days [DIR Art 107g(2)].1830 VII.C.4.3. Relationship between PSUR and risk management plan1831 The general relationship between the risk management plan (RMP) and the PSUR is described in1832 Module V, while an overview of the common RMP/PSUR modules is provided in VII.C.4.3.1..1833 During the preparation of a PSUR, the marketing authorisation holder should consider whether any1834 identified or potential risks discussed within the PSUR is important and requires an update of the RMP.1835 In these circumstances, updated revised RMP including the new important safety concern should be1836 submitted with the PSUR and assessed in parallel, following the timetable for the assessment of PSUR1837 as described above.1838 If important safety concerns are identified by the national competent authorities in the Member States1839 during the assessment of a PSUR and no updated RMP or no RMP has been submitted,1840 recommendations should be made to submit an update or a new RMP within a defined timeline.1841 VII.C.4.3.1. PSUR and risk management plan – common modules1842 The proposed modular formats for the PSUR and the RMP aim to address duplication and facilitate1843 flexibility by enabling common PSUR/RMP sections to be utilised interchangeably across both reports.1844 Common sections with the above mentioned reports are identified in Table VII.1.:1845 Table VII.1. Common sections between PSUR and RMP1846 PSUR section RMP section Section 3 – “Actions taken in the reporting interval for safety reasons” Part II, module SV – “Post-authorisation experience”, section “Regulatory and marketing authorisation holder action for safety reason” Sub-section 5.2 – “Cumulative and interval patient exposure from marketing experience” Part II, module SV – “Post-authorisation experience”, section “Non-study post- authorisation exposure” Sub-section 16.1 – “Summary of safety concerns” Part II, module SVIII – “Summary of the safety concerns” (as included in the version of the RMP which was current at the beginning of the PSUR reporting interval) Sub-section 16.4 – “Characterisation of risks” Part II, Module SVII – “Identified and potential
  • 58. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 58/69 PSUR section RMP section risks” Sub-section 16.5 – “Effectiveness of risk minimisation (if applicable)” Part V – “Risk minimisation measures”, section “Evaluation of the effectiveness of risk minimisation activities” VII.C.5. EU-specific requirements for periodic safety update reports1847 The scientific evaluation of the risk-benefit balance of the medicinal product included in the PSUR1848 detailed in VII.B.5. shall be based on all available data, including data from clinical trials in1849 unauthorised indications and populations according to the provisions of DIR Art 107b and IR Art 34(1).1850 The EU-specific requirements should be included in the PSUR EU regional appendix.1851 VII.C.5.1. PSUR EU regional appendix, sub-section “Proposed product1852 information”1853 The assessment of the need for amendments to the product information is incorporated within the1854 PSUR assessment procedure in the EU. The regulatory opinion/position should include1855 recommendations for updates to product information where needed. Marketing authorisation holders1856 should provide the necessary supportive documentation and references within the PSUR to facilitate1857 this.1858 Within the PSUR, the marketing authorisation holder is required to consider the impact of the data and1859 evaluations presented within the report, on the marketing authorisation. Based on the evaluation of1860 the cumulative safety data and the risk-benefit analysis, the marketing authorisation holder shall draw1861 conclusions in the PSUR as to the need for changes and/or actions, including implications for the1862 approved SmPC(s) for the product(s) for which the PSUR is submitted [IR Art 34 (5)].1863 In this sub-section, the marketing authorisation holder should provide the proposals for product1864 information (SmPC and package leaflet) based on the above mentioned evaluation. These should be1865 based on all EU authorised indications.1866 A track change version of the proposed SmPCs and package leaflets based on the assessment and1867 conclusions of the PSUR should be provided. For centrally authorised medicinal products, the proposed1868 product information should also be submitted to Module 1.3.1 of the Electronic Common Technical1869 Document (eCTD).1870 All the SmPCs and packages leaflets covered by the PSUR should be reviewed to ensure that they1871 reflect the appropriate information accordingly to the cumulative data included and analysed in the1872 PSUR.1873 Amendments to the product information should not be postponed or delayed until the PSUR submission1874 and amendments not related to the information presented in the PSUR, should not be proposed within1875 the PSUR procedure. It is the obligation of the marketing authorisation holder to submit a variation in1876 accordance with the Regulation (EC) No 1234/2008 on variations to the terms of a marketing1877 authorisation.1878 VII.C.5.2. PSUR EU regional appendix, sub-section “reference information comparison”1879 In this sub-section, the marketing authorisation holder should highlight any important differences1880 between the reference information in use and the proposals for product information in the EU.1881 Examples of important differences may be those relating to adverse drug reactions, contraindications,1882
  • 59. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 59/69 warnings, interactions and overdose. For the purposes of this comparison, the reference information in1883 effect at the end of the reporting interval may be used but the marketing authorisation holder should1884 highlight any important changes proposed/introduced in the time period between the data lock point1885 and submission of the PSUR.1886 VII.C.5.2. PSUR EU regional appendix, sub-section “Proposed additional1887 pharmacovigilance and risk minimisation activities”1888 Considering the provision established in IR Art 34 (5), this sub-section should include proposals for1889 additional pharmacovigilance and additional risk minimisation activities based on the conclusions and1890 actions of the PSUR, including a statement of the intention to submit a RMP or an updated RMP when1891 applicable.1892 VII.C.5.3. PSUR EU regional appendix, sub-section “Summary of ongoing1893 safety concerns”1894 In order to support the information provided in the PSUR section 16.1 “Summary of safety concerns”1895 (see VII.B.5.16.1.), Table 1.10 (according to the current RMP template) “Summary – Ongoing safety1896 concerns” should be included in this PSUR sub-section. This table should be extracted from the version1897 of RMP available at the beginning of the PSUR reporting interval (see Module V).1898 VII.C.5.4. PSUR EU regional appendix, sub-section “Reporting of results1899 from post-authorisation safety studies”1900 Findings from both interventional and non-interventional (for further guidance see Module VIII) post-1901 authorisation safety studies (PASS) should be reported in the PSUR. While the marketing authorisation1902 holder should inform competent authorities in Member States and the Agency as applicable about any1903 new information that may impact on the risk-benefit balance immediately, the PSUR should provide1904 comprehensive information on the findings of all PASS, both interventional and non-interventional, in1905 PSUR sections 7 and 8 respectively.1906 Final study reports for studies conducted with the primary aim of identifying, characterising or1907 quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the1908 effectiveness of risk management measures which were completed during the reporting interval should1909 also be included as an annex to the PSUR. For such studies discontinued during the reporting interval,1910 the reasons for stopping the study should also be explained.1911 If an important safety concern has been identified in the course of a study, regardless of whether it1912 has been detected through pre-specified methods and whether the study is considered a PASS, the1913 marketing authorisation holder and specifically the qualified person responsible for pharmacovigilance1914 (QPPV) will have informed the relevant competent authorities in Member States immediately.1915 PSURs should not be used as the initial communication method either for the submission of final study1916 reports to the competent authorities in Member States or for the notification of any new information1917 that might influence the evaluation of the risk-benefit balance.1918 VII.C.5.5. PSUR EU regional appendix, sub-section “Effectiveness of risk1919 minimisation”1920 Risk minimisation activities are public health interventions intended to prevent the occurrence of an1921 adverse drug reaction(s) associated with the exposure to a medicinal product or to reduce its severity1922 should it occur. The success of risk minimisation activities in delivering these objectives needs to be1923
  • 60. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 60/69 evaluated throughout the lifecycle of a product to ensure that the burden of adverse reactions is1924 minimised and hence the overall risk-benefit balance is optimised. In accordance with section1925 VII.B.5.16.5., evaluation of broad global experience should be reflected in the body of the report.1926 This sub-section should additionally provide an evaluation of the effectiveness of routine and/or1927 additional risk minimisation activities specifically relevant to an EU context. This should take account of1928 regulatory imposed obligations for implementation of risk minimisation measures in addition to the1929 overall requirement for monitoring of safety and benefit-risk. Results of any studies to assess the1930 impact or other formal assessment(s) of risk minimisation activities in the EU should be included when1931 available. As part of this critical evaluation, the marketing authorisation holder should make1932 observations on factors contributing to the success or weakness of risk minimisation activities. If a1933 particular risk minimisation strategy proves ineffective, then alternative activities need to be put in1934 place. In certain cases, it may be judged that risk minimisation cannot control the risks to the extent1935 possible to ensure a positive risk-benefit balance and that the medicinal product needs to be withdrawn1936 either from the market or restricted to those patients in whom the benefits outweigh the risks. More1937 extensive guidance on monitoring the effectiveness of risk minimisation activities is included in Module1938 XVI. As a principle, the marketing authorisation holder should distinguish in their evaluation between1939 implementation success and attainment of the intended outcome.1940 VII.C.6. Quality systems and record management systems for PSURs in the1941 EU network1942 VII.C.6.1. Quality systems and record management systems at the level of1943 the marketing authorisation holder1944 Specific quality system procedures and processes shall be in place in order to ensure the update of1945 product information by the marketing authorisation holder in the light of scientific knowledge, including1946 the assessments and recommendations made public via the European medicines web-portal, and on1947 the basis of a continuous monitoring by the marketing authorisation holder of information published on1948 the European medicines web-portal [IR Art 11(1)(f)].1949 It is the responsibility of the marketing authorisation holder to check regularly the list of EU reference1950 dates and frequency of submission published in the European medicines web-portal to ensure1951 compliance with the PSUR reporting requirements for their medicinal products (see VII.C.3.).1952 Systems should be in place to schedule the production of PSURs according to:1953  the list of EU reference dates and frequency of PSURs submission; or1954  the conditions laid down in the marketing authorisation; or1955  the standard PSUR submission schedule established according to DIR Art 107c(2) for products1956 authorised before 2 July 2012 (for centrally authorised products) and 21 July 2012 (for nationally1957 authorised products) as applicable (without any conditions in their marketing authorisation or not1958 included in the list of EU references dates and frequency of submission or not affected by the1959 derogation established in [DIR Art 107b(3)]); or1960  ad hoc requests for PSURs by a competent authority in a Member State or the Agency.1961 For those medicinal products where the submission of an RMP is not required, the marketing1962 authorisation holder should maintain on file a specification of important identified risks, important1963 potential risks and important missing information in order to support the preparation of the PSURs.1964
  • 61. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 61/69 The marketing authorisation holder should have procedures in place to follow the requirements1965 established by the Agency for the submission of PSURs.1966 The QPPV shall be responsible for the establishment and maintenance of the pharmacovigilance system1967 [DIR Art 104(e)] and therefore should ensure that the pharmacovigilance system in place enables the1968 compliance with the requirements established for the production and submission of PSURs. In relation1969 to the medicinal products covered by the pharmacovigilance system, specific additional responsibilities1970 of the QPPV in relation to PSURs should include:1971  ensuring the necessary quality, including the correctness and completeness, of the data submitted1972 in the PSURs;1973  ensuring full response according to the timelines and within the procedure agreed (e.g. next PSUR)1974 to any request from the competent authorities in Member States and the Agency related to PSURs;1975  awareness of the PSUR and assessment report conclusions, PRAC recommendations, CHMP1976 opinions, CMDh positions and European Commission decisions in order to ensure that appropriate1977 action takes place.1978 The record retention times for product-related documents in Module I also apply to PSURs and source1979 documents related to the creation of PSURs, including documents related to actions taken for safety1980 reasons, clinical trials and post-authorisation studies, relevant benefit information and documents1981 utilised for the calculation of patient exposure.1982 VII.C.6.2. Quality systems and record management systems at the level of1983 the European Medicines Agency1984 The application of the Agency’s quality system (see Module I) should support compliance by the1985 Agency when fulfilling its tasks and responsibilities for the management of PSUR procedures and EU1986 single assessments.1987 The Agency should have in place a process to technically validate the completeness of PSUR1988 submissions.1989 Line listings and summary tabulations from the EudraVigilance database utilised to support the PSUR1990 assessment should be created using reports by means of the EudraVigilance data analysis system.1991 Effective communication and circulation of PSURs and related documents is crucial for the successful1992 completeness of the procedure; therefore processes have to be in place for the circulation of1993 documents between the Agency, marketing authorisation holders, the Commission and the competent1994 authorities in Member States. Where applicable, the procedures should establish the necessity for1995 quality checks with the aim to remove any information of a personal or commercially confidential1996 nature.1997 Written procedures should reflect the different steps to follow for the maintenance of the list of EU1998 references dates and frequency of submission of PSURs published by the Agency in the European1999 medicines web-portal (see VII.C.3.).2000 Prior to the publication of summaries of PSUR assessment reports in the European medicines web-2001 portal (see VII.C.7.) the appropriate personnel at the Agency should adhere to the procedures2002 established for web publication of documents produced by the Agency or competent authorities in the2003 Member States.2004 All records related to PSURs created by the Agency’s staff members, experts or consultants are the2005 property of the Agency and all PSURs and related documents received are in the custody of the2006
  • 62. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 62/69 Agency. Both types of PSURs records (created or received by the Agency) are subject to the Agency’s2007 overall control via the PSUR repository set up according to the provisions laid down in REG Art 25a.2008 The Agency’s policy on records management (EMEA/590678/2007)22 , provides the basis for a2009 consistent, sustainable and efficient records management program and it has been developed in2010 accordance with the commonly recognised international standard for records management, “ISO2011 15489-1:2001 Information and documentation – Records management23 ”. According to the records2012 classification stated by the Agency’s policy, PSURs would be considered business, legal, evidential and2013 research/historical value records.2014 The record retention times for product-related documents in Module I also apply to PSUR- system2015 related documents (e.g. standard operating procedures) and PSUR -related documents (e.g. PSURs,2016 assessment reports, the data retrieved from the EudraVigilance database or other data used to support2017 the PSUR assessment).2018 VII.C.6.3. Quality systems and record management systems at the level of2019 the competent authorities in Member States2020 Each competent authority in the Member States shall have in place a pharmacovigilance system [DIR2021 Art 101] for the surveillance of medicinal products and for receipt and evaluation of all2022 pharmacovigilance data including PSURs. For the purpose of operating its tasks relating to PSURs in2023 addition to the pharmacovigilance system the national competent authorities in Member States should2024 implement a quality system (see Module I).2025 Competent authorities in the Member States should monitor marketing authorisation holders for2026 compliance with regulatory obligations for PSURs. Additionally, competent authorities should exchange2027 information in cases of non-compliance and take appropriate regulatory actions as required.2028 No PSUR assessment at EU level is foreseen for purely nationally authorised products authorised in2029 only one Member State; therefore the national competent authority in the Member State where the2030 medicinal product is authorised should have procedures in place for the assessment of PSURs related2031 to those medicinal products.2032 The procedures established by the national competent authorities in Member States for the2033 performance of the EU single assessment of PSURs, should be in line with the procedures established2034 by the Agency for the coordination of PSUR assessment in the EU regulatory network (see VII.C.4.).2035 These procedures should establish effective communication across the EU regulatory network and the2036 actions to be taken regarding the variation, suspension or revocation of the marketing authorisation2037 following the PRAC recommendations, CHMP opinion, CMDh position and European Commission2038 decision as applicable.2039 The procedures established by the Agency for the use of the PSUR repository to support the single2040 assessment, should be followed by the national competent authorities in Member States.2041 Where tasks related to PSUR procedures are delegated to third parties, the national competent2042 authorities in Member States should ensure that they are subject to a quality system in compliance2043 with the obligations provided by the European legislation.2044 The record retention times for product-related documents in Module I also apply to PSUR- system2045 related documents (e.g. standard operating procedures) and PSUR -related documents (e.g. PSURs,2046 assessment reports, the data retrieved from the EudraVigilance database or other data used to support2047 the PSUR assessment).2048 22 www.ema.europa.eu 23 www.ISO.org
  • 63. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 63/69 VII.C.7. Transparency2049 VII.C.7.1. Publication of PSUR-related documents on the European2050 medicines and national medicines web-portals2051 The following documents shall be made publicly available by means of the European medicines web-2052 portal [DIR Art 107l, REG Art 26(g)]:2053  list of EU reference dates and frequency of submission of PSURs (see VII C.3.);2054  final assessment conclusions of the adopted assessment reports;2055  PRAC recommendations including relevant annexes;2056  CMDh position including relevant annexes and where applicable, detailed explanation on scientific2057 grounds for any differences with the PRAC recommendations;2058  CHMP opinion including relevant annexes and where applicable, detailed explanation on scientific2059 grounds for any differences with the PRAC recommendations;2060  European Commission decision.2061 The version and date of publication are reflected in each document as they define the issue of the2062 PRAC recommendations, CHMP opinions, CMDh positions and European Commission decisions at a2063 certain point of time.2064 Links between the European medicines web-portal and the National medicines web-portals should be2065 made whenever possible and relevant.2066 Any personal or confidential data made public by the Agency or the competent authorities in Member2067 States as referred to in paragraphs 2 and 3 of Article 106a of Directive 2001/83/EC shall be deleted2068 unless considered necessary in terms of protection of the public health [DIR Art 106a(4)].2069 VII.C.8. Renewal of marketing authorisations2070 Marketing authorisations need to be renewed after 5 years on the basis of a re-evaluation of the risk-2071 benefit balance in order to continue to be valid to place the product on the market. This renewal is2072 irrespective of whether the marketing authorisation is suspended. Further details on the procedure and2073 the documentation requirements can be found in the current versions of the “Guideline on Processing2074 of Renewals in the Centralised Procedure” (EMEA/CHMP/2990/00) for Centralised products and the2075 “CMDh Best Practice Guide on the processing of renewals in the MRP/DCP” (CMDh/004/2005) for other2076 products.2077 No PSURs, addendum reports and summary bridging reports should be submitted within the renewal2078 application. The clinical overview should include an addendum containing the relevant sections for the2079 re-assessment of the risk-benefit balance of the medicinal product. These sections are identified in the2080 above-mentioned guidelines for renewal. Marketing authorisation holders are advised to consider this2081 GVP Module VII as guidance for the preparation of the addendum to the clinical overview.2082 Following the submission of a renewal application, the PRAC may be consulted for medicinal products2083 authorised through the centralised procedure as regards safety issues. For nationally authorised2084 products, including those authorised through the mutual recognition or decentralised procedure, the2085 PRAC may also be consulted upon request by a competent authority in a Member State on the basis of2086 safety concerns.2087
  • 64. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 64/69 Conditional marketing authorisations should be renewed annually [REG Art 14(7)]. Further details on2088 the procedure and the documentation to be submitted can be found in the “Guideline on the scientific2089 application and the practical arrangements necessary to implement Commission Regulation (EC) No2090 507/2006 on the conditional marketing authorisation for medicinal products for human use falling2091 within the scope of regulation (EC) no 726/2004” ( EMEA/509951/2006).2092 VII.C.9. Transition and interim arrangements2093 VII.C.9.1. Submission and availability of documents before the Agency’s2094 repository is in place2095 The Agency shall, in collaboration with the competent authorities in Member States and the European2096 Commission set up and maintain a repository for PSURs and the corresponding assessment reports so2097 that they are fully and permanently accessible to European Commission, the competent authorities in2098 Member States, the PRAC, the CHMP and the CMDh [REG Art 25a].2099 The repository shall undergo an independent audit before the functionalities are announced by the2100 Agency’s management board [REG Art 25a].2101 As established in the transitional provisions introduced in Directive 2010/84/EU Art 2(7), until the2102 Agency can ensure the functionalities agreed for the repository, marketing authorisation holders under2103 the obligation to submit PSURs irrespective of whether the medicinal product is authorised in one or2104 more Member States and irrespective of whether the active substance or combination of active2105 substances is on the EU reference date list shall submit the PSURs to all competent authorities in2106 Member States in which the medicinal products are authorised. For the substances or combination of2107 active substances subject to a single assessment or for which an EU reference date has been2108 established, the PSURs should be also sent to the Agency.2109 The competent authorities in Member States requirements for the submission of PSURs during this2110 transitional period are published in the Agency web-site24 .2111 From 12 months after the functionalities of the repository have been established and have been2112 announced by the Agency, the marketing authorisation holders shall submit the PSURs electronically to2113 the Agency regardless of the authorisation procedure of the medicinal product [DIR Art 107b(1)]. The2114 competent authorities in Member States shall ensure that this obligation applies as required [DIR Art2115 2(7)].2116 Once the structured electronic format “ePSUR”, based on content agreed in the ICH-E2C(R2), becomes2117 available, marketing authorisation holders will have the possibility to submit PSURs and related2118 documents automatically via an electronic gateway.2119 Until the repository is in place, the following documents should be circulated through a dedicated2120 mailbox or according to the instructions for submissions published by the Agency:2121  preliminary assessment report created by the PRAC Rapporteur/Member State within 60 days of2122 the start of the procedure. The report should be circulated to the Agency and the members of the2123 PRAC. The Agency should send the report to the concerned marketing authorisation holder(s);2124  comments submitted by the marketing authorisation holders(s) and members of the PRAC by Day2125 90 on the PRAC Rapporteur/Member State preliminary assessment report. These comments should2126 also be circulated to all members of the PRAC by the marketing authorisation holder.2127 24 www.ema.europa.eu
  • 65. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 65/69  updated PRAC Rapporteur/Member State assessment report created within 15 days (i.e. by Day2128 105) should be forwarded to the Agency and members of the PRAC.2129 Further to adoption, the Agency should send the CHMP opinion together with its annexes and2130 appendices to the European Commission, marketing authorisation holder(s) and competent authorities2131 in Member States, through secure email until the repository is in place.2132 VII.C.9.2. Quality systems and record management systems at the level of2133 the competent authorities in Member States2134 Special considerations should be taken for the management of the PSURs submitted to the concerned2135 competent authorities in Member States until the Agency can ensure the functionalities agreed for the2136 PSUR repository and 12 months after the establishment of the repository according to the transitional2137 provisions.2138 VII.C.9.3. Publication of the EU list of union references dates and start of2139 the EU-PSUR single assessment procedure2140 As stated in VII.C.3.6., the list of EU reference dates and frequency of submission should be published2141 in the European medicines web-portal, nevertheless, the EU single assessment procedure for2142 substances included only in nationally authorised products, detailed in VII.C.4.2.2., and VII.C.4.2.4.2143 will be delayed until funds are available.2144 2145 2146
  • 66. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 66/69 VII.APPENDICES2147 VII.Appendix 1. Examples of tabulations for estimated exposure and2148 adverse events/reactions data2149 Marketing authorisation holders can modify these examples tabulations to suit specific situations, as2150 appropriate.2151 Table VII.2. Estimated cumulative subject exposure from clinical trials2152 Estimates of cumulative subject exposure, based upon actual exposure data from completed clinical2153 trials and the enrolment/randomisation schemes for ongoing trials.2154 Treatment Number of Subjects Medicinal product Comparator Placebo 2155 Table VII.3. Cumulative subject exposure to investigational drug from completed clinical trials by age2156 and sex2157 Number of subjects Age range Male Female Total Data from completed trials as of [date]2158 Table VII.4. Cumulative subject exposure to investigational drug from completed clinical trials by2159 racial/ethnic group2160 Racial/ethnic group Number of subjects Asian Black Caucasian Other Unknown Total Data from completed trials as of [date]2161 Table VII.5. Cumulative exposure from marketing experience2162 Indication Sex Age (years) Dose Formulation Region Male Female 2to≤16 >16to65 >65 Unknown <40 ≥40 Unknown Intravenous Oral EU Japan Colombia US/Canada Other Overall Depression Migraine
  • 67. Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1) EMA/816292/2011 Rev 1 Page 67/69 Table VII.5 includes cumulative data obtained from day/month/year throughout day/month/year, where available2163 Table VII.6. Interval exposure from marketing experience2164 Indication Sex Age (years) Dose Formulation Region Male Female 2to≤16 >16to65 >65 Unknown <40 ≥40 Unknown Intravenous Oral EU Japan Colombia US/Canada Other Depression Migraine Table VII. 6 includes interval data obtained from day/month/year throughout day/month/year2165 Table VII.7. Cumulative tabulation of serious adverse events from clinical trials2166 System Organ Class Preferred Term Investigational medicinal product Blinded Active comparator Placebo Blood and lymphatic system disorders Anaemia Bone marrow necrosis Cardiac disorders Tachycardia Ischaemic cardiomyopathy 2167 Table VII.8. Numbers of adverse reactions by preferred term from post-authorisation sources*2168 SOC MedDRA PT Spontaneous, including competent authorities (worldwide) and literature Non-interventional post- marketing study and reports from other solicited sources ** Serious Non-serious Total Spontaneous Serious Interval Cumulative Interval Cumulative Cumulative Interval Cumulative <SOC 1> <PT> <PT> <PT> <SOC 2> <PT> <PT> <PT> <PT> * Non-interventional post-authorisation studies, reports from other solicited sources and spontaneous ICSRs (i.e.,2169 reports from healthcare professionals, consumers, competent authorities (worldwide), and scientific literature)2170 ** This does not include interventional clinical trials.2171
  • 68. Guideline on good pharmacovigilance practices (GVP) – Module VII EMA/252670/20122 Page 68/69 VII.Appendix 2. Example of tabular summary of safety signals that were2172 ongoing or closed during the reporting interval2173 The tabular summary below is a fictitious example.2174 Table VII.9. Tabular summary of safety signals ongoing or closed during the reporting interval2175 Reporting interval: DD-MMM-YYYY to DD-MMM-YYYY2176 2177
  • 69. Guideline on good pharmacovigilance practices (GVP) – Module VII EMA/252670/20122 Page 69/69 Explanatory notes:2178 Signal term:2179  A brief descriptive name of a medical concept for the signal. This may evolve and be refined as the2180 signal is evaluated. The concept and scope may or may not be limited to specific MedDRA term(s),2181 depending on the source of signal.2182 Date detected:2183  Month and year the marketing authorisation holder became aware of the signal.2184 Status:2185  Ongoing: Signal under evaluation at the data lock point of the PSUR. Anticipated completion date,2186 if known, should be provided.2187  Closed: Signal for which evaluation was completed before the data lock point of the PSUR.2188 Note: A new signal of which the marketing authorisation holder became aware during the reporting2189 interval may be classified as closed or ongoing, depending on the status of the signal evaluation at the2190 end of the reporting interval of the PSUR.2191 Date closed:2192  Month and year when the signal evaluation was completed.2193 Source of signal:2194  Data or information source from which a signal arose. Examples include, but may not be limited to,2195 spontaneous reports, clinical trial data, scientific literature, and non-clinical study results, or2196 information request or inquiries from a competent authority (worldwide).2197 Reason for evaluation and summary of key data:2198  A brief summary of key data and rationale for further evaluation.2199 Action(s) taken or planned:2200 State whether or not a specific action has been taken or is planned for all closed signals that have been2201 classified as potential or identified risks. If any further actions are planned for newly or previously2202 identified signals under evaluation at the data lock point, these should be listed, otherwise leave blank2203 for ongoing signals.2204