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Road towards GVP VII Rev II - Explanatory note updates

Explanatory notes updates on Good pharmacovigilance practices Module VII: Periodic Safety Update Report

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Road towards GVP VII Rev II - Explanatory note updates

  1. 1. Road towards GVP VII: PSUR (Rev 2) update Dr. Rohith K Nair Updates from PSUR explanatory notes
  2. 2. Disclaimer • The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to the organization that presenter is/was affiliated with. • These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws. Used by permission. All rights reserved.
  3. 3. Abbreviation AR Assessment Report CA Competent Authority CAP Centrally Authorised Product CHMP Committee for Medicinal Product for Human Use CMDh Coordination Group for Mutual Recognition and Decentralised Procedures – Human DLP Data Lock Point DCP Decentralized procedure EC European Commission EMA European Medicines Agency MA Marketing Authorisation MAH Marketing authorisation holder MS Member State MRP Mutual Recognition procedure NAP Nationally Authorised Product PRAC Pharmacovigilance Risk Assessment Committee PSUR Periodic Safety Update Report
  4. 4. Applicability • The following discussion is mainly applicable for the periodic reports which comes within the EU guidance “Guideline on good pharmacovigilance practices (GVP): Module VII – Periodic safety update report (Rev 1)” • Out of scope • Guideline on good pharmacovigilance practices (GVP): Module V – Risk management systems (Rev 2) • Guideline on good pharmacovigilance practices (GVP): Module IX – Signal management (Rev 1)
  5. 5. Topics for discussion • Section 1: PSUR • History of PSUR • PSUR preparation • PSUR submission • PSUR Assessment • PSUR Outcomes • Section 2: Explanatory note updates • PSUR Explanatory notes
  6. 6. Introduction to PSUR • Periodic safety update reports (PSURs) are pharmacovigilance documents intended to provide an evaluation of the risk-benefit balance of a medicinal product for submission by marketing authorisation holders at defined time points during the post-authorisation phase. • Main objective - present a comprehensive, concise, and critical analysis of new or emerging information on the risks of the medicinal product. • A tool for post authorisation evaluation at defined time points in the lifecycle of a product • To assess whether any action concerning the MA for the medicinal product is necessary. • Considers the safety data of a product towards its exposure to the patients. • The final assessment of PSURs may lead to the product information changes.
  7. 7. History of PSURs 1992 • CIOMS II Guideline on PSURs published 1996 • Step 4 – ICH E2C Guideline - Clinical Safety Data Management - Periodic Safety Update Reports for Marketed Drugs 2003 • Step 4 - Addendum to ICH E2C (R1) published 2012 • ICH guideline E2C (R2) on periodic benefit-risk evaluation report (PBRER) • GVP VII first version effective 2013 • GVP VII: Revision 1 effective 2017 • PSUR roadmap: joint industry/assessor training • Explanatory Note to GVP Module VII
  8. 8. PSUR timelines • It is the responsibility of MAH to submit PSURs for its own products according to the following timelines: • 70 calendar days of the data lock point - PSURs covering intervals up to 12 months • 90 calendar days of the data lock point - PSURs covering intervals in excess of 12 months • As requested by CA/90 days - timeline for the submission of ad hoc PSURs
  9. 9. EURD List • EURD = European Union Reference Date list for PSUR submissions • Why - • Harmonisation of data lock point and frequency of submission of PSURs • Optimisation of the management of PSURs and PSURs assessments • Single EU assessment and reassessment of the risk-benefit balance • Periodicity is defined on the basis of a risk-based approach • Data lock points included in the list of EU references dates enable the synchronisation of PSURs submission for products subject to different marketing authorisations and permit the EU single assessment
  10. 10. EURD List • EURD list - expected to be updated monthly • Any change to the dates of submission and frequency takes effect 6 months after the publication date. • Information included in the list may need to be updated when considered necessary by the CHMP or CMDh after consultation with the PRAC
  12. 12. PSUR preparation - sources • non-clinical studies • spontaneous reports (e.g. on the marketing authorisation holder’s safety database) • active surveillance systems (e.g. sentinel sites) • investigations of product quality • product usage data and drug utilisation information • clinical trials, including research in unauthorised indications or populations • observational studies, including registries ▪ patient support programs ▪ systematic reviews and meta-analysis; ▪ marketing authorisation holders sponsored websites5 ▪ published scientific literature or reports from abstracts, including information presented at scientific meetings ▪ unpublished manuscripts ▪ licensing partners, other sponsors or academic institutions and research networks ▪ competent authorities (worldwide)
  13. 13. PSUR content • Structure - Regulation 520/2012, GVP Module VII, ICH E2C(R2) provide the guideline on the format and structure • The format and table of contents of all PSURs shall be as described in the IR Art 35 and each report should include interval as well as cumulative data • Content and Format • Part 1: Title page including signature • Part 2: Executive Summary • Part 3: Table of Contents – Subsections mentioned in upcoming 3 slides
  14. 14. Table of Contents
  15. 15. Table of Contents
  16. 16. Table of Contents
  17. 17. PSUR Submissions MAH CA
  18. 18. Conditions for PSUR submissions
  19. 19. Submission of PSURs • The amended Directive 2001/83/EC also waives the obligation to submit PSURs routinely for: • Generic medicinal products (authorised under DIR Art 10(1)) • Well-established use medicinal products (authorised under DIR Art 10a) • Homeopathic medicinal products (authorised under DIR Art 14) • Traditional herbal medicinal products (authorised under DIR Art 16a), [DIR Art 107b(3)]
  20. 20. Submission of PSURs • As of June 2016, MAHs are required to submit all PSURs in the EU to the central PSUR repository. • Use of the PSUR repository is mandatory – single assessment or National procedure. • A single assessment of related PSURs is carried out for medicines that contain the same active substance or combination of active substances, as per EURD list.
  21. 21. PSUR Repository •Central storage space for PSUR, AR and recommendations •Enhanced data collection •Easy access •Faster assessments •PSURs and Cover letters •PSUR AR •PRAC recommendations •EC •NCA •PRAC and CHMP members •EMA •MAHs – restricted access •Regulation (EC) 726/2004 •Directive 2001/83/EC Legal reference Access Advantages Storage space Central platform for PSURs
  22. 22. Total PSUR submissions
  23. 23. PSUR Assessments
  24. 24. Periodic safety update report single assessments • The outcomes of single assessments of periodic safety update reports (PSURs) for active substances or combinations of active substances contained in medicines authorised in the European Union (EU) are published by EMA. • Single Assessment Reports of PSURs are shared among all Marketing Authorisation Holders involved in the concerned procedure. • PSUR single assessment procedure leads to a variation of marketing authorisation – MAHs with national authorisation should submit a variation to align their marketing authorisation with the single assessment outcome, even if their product was not in the direct scope of the procedure.
  25. 25. Assessor timetable Day Action Day 0 Start of the procedure according to the published timetable Day 60 PRAC Rapporteur’s / Member State preliminary assessment report Day 90* MAH and PRAC members’ / Member States comments Day 105 PRAC Rapporteur’s / Member State updated assessment report (if necessary) Day 120 PRAC recommendation adoption with the final PRAC assessment report Day 134 CHMP opinion / CMDh position (in case PRAC recommends a variation, suspension or revocation of the MA) *MAH to respond to the outstanding issues/questions from PRAC/MS
  26. 26. Steps of assessment
  27. 27. Outcomes of PSUR PRAC recommendation CAP only CHMP adopts the PRAC decision CAP and NAP CHMP adopts PRAC decision NAP only CMDH adopts the PRAC decision If variation, suspension or revocation is recommended for the MA
  28. 28. PSUR outcomes – where to find? Outcomes of PSUR assessment CAP EPAR page of the relevant medicine CAP/NAP Community register for NAP EU single assessment EMA website
  29. 29. Types of Outcomes: • Maintenance • Variations* • Amendment of Product Information *Update of RMP or Data request/analysis in the upcoming PSUR can also be recommended from the PRAC/CA
  30. 30. Current Scenario • Joint industry/assessor training for PSUR – Webinar published in the EMA website • Explanatory note – published in the EMA website • PSUR roadmap elements discussed in 7th industry stakeholder platform meeting – near to completion. • GVP VII – Periodic Safety Update Report – Rev 2 – Publishing awaited.
  31. 31. PSUR explanatory notes – Why? • Posed a number of challenges that are specific to the assessment of nationally authorised medicinal products. • Addressing the challenges encountered during the two years of running the PSUSA process • The explanatory note will serve as the basis for the update of GVP Module VII, which will eventually replace it.
  32. 32. Updates from explanatory notes • QPPV to ensure the logical content and flow during the preparation of PSUR. PSURs to be provided in English. • MAH to tailor the level of detail from section 6 to 16 based on clinical significance. • PSUR is not intended for the notification of urgent new safety or efficacy information. • If significant actions have been taken in any country of the world for safety reasons in the reporting interval of a PSUR, they should be described in sufficient detail.
  33. 33. Updates from explanatory notes • The reference product information should be provided in English • The European legislation states that based on the evaluation of the cumulative safety data and the benefit/risk balance analysis, the MAH shall draw conclusions regarding the need for changes and/or actions, including any implications for the approved PI for the medicinal product(s) for which the PSUR has been submitted. • MAH of authorisations granted under Article 10 of the Directive 2001/83/EC should ensure that they have aligned their PI in full to their reference medicinal product prior to the PSUR submission date • The number of patients exposed should preferably be provided alongside the exposure length (preferably number of patients or patient/year). The method should be explained.
  34. 34. • Any discrepancies in the summary tabulations should be explained and justified. • In Late-breaking information, any relevant safety related procedure should be mentioned in this section (e.g. the start of a referral procedure or important issues occurring after DLP • Overview of signals: new, ongoing, or closed • In the review of PSURs so far, a number of deficiencies have been noted including the absence of cumulative reviews requested in a previous PSUR, or a signal refuted without an appropriate explanation. • A NCA may request that a specific topic (not considered a signal) should be monitored and reported in the PSUR. The MAH should summarise the result of the analysis in section 15 of the PSUR, if it is negative. Updates from explanatory notes
  35. 35. Updates from explanatory notes • If the result of the analysis is negative, MAHs may propose to discontinue specific monitoring in future PSURs. • If the specific topic becomes a signal, it should be included in the signal tabulation (section 16) • It is agreed that monitoring through routine pharmacovigilance will be appropriate once a topic has been sufficiently monitored and a safety signal has not been identified. • When safety issues (not considered a signal or important risk) are followed-up in subsequent PSURs, the interval data should be put in the context of the cumulative data.
  36. 36. Updates from explanatory notes • Signal assessment should be made on the basis of an aggregate review of cumulative data available to the MAH. • A summary of safety concerns specific to the PSUR/substance(s) at the start of the reporting interval should be provided, taking into account that the PSUR is a document submitted globally. • Risk Management Plan: • For which there is an EU-Risk Management Plan (RMP) in place, summary of safety concerns outlined in the EU RMP at the beginning reporting interval is expected to be included as a minimum. In the EU regional appendix in GVP Module section VII.C.5.3 the RMP version number should be provided as well as an explanation for any differences or additional safety concerns in section 16.1 of the PSUR compared to the EU
  37. 37. Updates from explanatory notes For a product for which no EU RMP is in place, the considerations below should be taken into account in order to determine what constitutes an important identified or potential risk or missing information (i.e. safety concerns). • This section should not be an extensive listing of all labelled adverse reactions and therefore could be very brief. • It should concentrate on important safety concerns/missing information at the start of the reporting interval. • A justification for each inclusion should be provided for a product where there is no EU RMP available. For products without an EU RMP, GVP Module VII states that in section 16.1 the MAHs should provide information on the important identified and potential risks as well as missing information.
  38. 38. Updates from explanatory notes • PSUR per se is not a tool for harmonisation of the list of safety concerns. • Risk minimisation measures • The results of the evaluation of the effectiveness of risk minimisation activities in place should be presented. • Based on this evaluation, the MAH should propose the implementation of further measures/ amendments to existing ones and/or consider the relevance of maintaining or removing the related safety concern • Use of EudraVigilance data by MAHs during the preparation of PSURs – from 22 November 2017.
  39. 39. Updates from explanatory notes • Whenever there are signals evaluations in the PSUR triggered by other sources of information or there are issues under close monitoring, it is expected that the data from EudraVigilance is considered in order to complement and enhance the signal assessment. • MAH should not include new efficacy/effectiveness information that only confirms what was already known for the product. • Assessment of the PSUR should not conclude on evidence of efficacy in new indications.
  40. 40. Updates from explanatory notes • Although section 16.4 of GVP Module VII currently mentions the modules should be the same, this is no longer a requirement since the publication of GVP Module V Rev.2. This aspect will be further clarified in the upcoming revision of GVP Module VII.
  41. 41. Conclusion 1. The explanatory note will serve as the basis for the update of GVP Module VII, which will eventually replace it. 2. MAHs to tailor the level of detail (from section 6 to 16) in PSUR based on clinical significance. 3. PSUR not to be used for harmonisation of safety concerns or notification of urgent new safety or efficacy information. 4. Summary of safety concerns specific to the PSUR/substance(s) at the start of the reporting interval should be provided. 5. Data from Eudravigilance considered mandatory to complement the preparation of PSUR. 6. PSURs and RSI to be provided in English. 7. The PSUR and RMP common sections no longer a requirement, since GVP V is revised and GVP VII update is yet to be published.
  42. 42. References • uideline/2013/04/WC500142468.pdf • uideline/2017/04/WC500225264.pdf • s/events/2017/08/event_detail_001502.jsp&mid=WC0b01ac058004d5c3 • • psur • s/events/2017/08/event_detail_001501.jsp&mid=WC0b01ac058004d5c3