PSUR and PSUR repository. Legal basis. PSUR/PBRER General comments

Transcription

1 PSUR and PSUR repository Mag. Dr. Irmgard Resch Dep. Assessment Pharmacovigilance AGES-Gespräche Vienna, Österreichische Agentur für Gesundheit und Ernährungssicherheit GmbH Legal basis Regulation (EU) No 1235/2010 amending Regulation (EC) No 726/2004 and Directive 2010/84/EU amending Directive 2001/83/EC, which apply from July 2012 AMG Pharmakovigilanz-Verordnung (2013) GVP-Module Guidelines on good pharmacovigilance practices (Module VII) 2 PSUR/PBRER General comments Periodic Benefit Risk Evaluation Report (PBRER) described in the ICH-E2C(R2) guideline. PBRER replaces format described in ICH-E2C(R1). Risk based periodicity European Union Reference Date list (EURD) Not routinely required for low risk/old products by - generic medicinal products (DIR Art 10(1)) - well-established use medicinal products (DIR Art 10a) (- homeopathic medicinal products (DIR Art 14)) (- traditional herbal medicinal products (DIR Art 16a)) Single assessments of PSUSAs have started EU repository has been established 3 1

2 A PSUR is required for drugs with Full MA (Vollzulassung) / hybrid application Condition in the MA Yes in the, even if no full MA column: Are PSURs required for products referred to in Articles 10(1), 10a, 14, 16a of Directive 2001/83/EC as amended? YES/NO Article 10(1): Generic applications Article 10a: Well-established medicinal use (for 10 years) Article 14: Homeopathic medicinal products (orally or externally, no specific therapeutic indication, sufficient degree of dilution) Article 16a: Traditional herbal medicinal product 4 Products authorisedbefore 02 July 2012 (centrally authorised) and 21 July 2012 (nationally authorised) frequency and dates of submission of PSURs not laid down as a condition to the MA or in shall submit PSURs according to the following submission schedule at 6 months intervals once the product is authorised, even if it is not marketed; once a product is marketed, 6 monthly PSUR submission should be continued following initial placing on the market in the EU for 2 years, then once a year for the following 2 years and thereafter at 3-yearly intervals. 5 How to write a PSUR (PBRER)? Use the structureas provided in the GVP Module VII Write from a risk-basedview -- Most important sections are: ---Sales information ---Change of Reference Safety information(rsi) ---Adverse events as reported from spontaneouscases, solicited sources, literature, clinical trials ---Summary of safety concerns Write PSUR (PBRER) as a stand-alone document 6 2

3 How to submit a PSUR (PBRER)? On CD with a cover letter to AGES or via CESP, not as a paper copy From 13 June 2016: all PSURs have to be submitted to the PSUR repository 7 was developed using the following data sources: the Eudravigilance Medicinal Product Dictionary (EVMPD) and the PSUR Work Sharing (WS) and Synchronisation lists. The first publication of the took place on 1st October The EU single assessment with CAPs and NAPs started in April Single assessment for NAPs only started in January is a dynamic document frequently updated in response to regulatory changes but also to constantly improve the clarity on the scope of each procedure and integration with the Article 57 database (xevmpd). For newly authorised products, the 1st PSUR submitted in the EU cannot cover a period longer than 6 months CAP =Centrally authorised products NAP =Nationally auth. products 8 List of Union reference dates and frequency of submission of periodic safety update reports Comprehensive list of active substances and combinations of active substances contained in medicinal products subject to different marketing authorisations, with the corresponding EU reference dates frequencies for submission of PSURs related data lock points Information takes effect six months after the publication date Marketing-authorisation holders are requested to submit PSURs to national competent authorities or the Agency according to the dates published in the. and_events/news/2012/09/news_detail_ jsp&mid=wc 0b01ac058004d5c1 9 3

4 GVP Module VII Periodic Safety Update Report is legally binding MAHs should submit a PSUR in accordance with the published submission deadline where it concerns an active substance or combination of active substances listed in the, even if marketed in only one Member State, unless exempted from submission e.g. generic and wellestablished use medicinal products. MAH has a product which is authorisedonly in one country, should also follow the. 10 EU-single assessment (PSUSA) For different marketing authorisations containing the same active substance or the same combination and for which the frequency and dates of submission of PSURs have been harmonised in the. These PSURs will be jointly assessed by a Member State appointed by the CMDh and results in one single assessment report, which will be shared amongst all the MAHs whose medicinal product(s) are part of the PSUR single assessment procedure. Non-EU-single assessments: authorised only in one country and those substances which do not appear on the 11 Active substances and combinatio ns of active substances European Union reference date (EURD) PSUR Submission Frequency DLP Submission date Lactitol 03/09/ years

5 Next DLP (For active substances or combinatio n of active substances with a PSUR frequency of less than one year) Next Submission date Are PSURs required for products referred to in Articles 10(1), 10a, 14, 16a of Directive 2001/83/E C as amended? Yes/No Publication Date (in accordance with Article 107c(7) of Directive 2001/83/E C as amended) Notes No Lead MS added on 12/05/ Procedure number of the PSUR single assessment (DLP) PSUSA/ / Procedure number of the PSUR single assessment Procedure (Next DLP) PRAC represent ative of the PSUR single assessment Procedure Jan Neuhauser (Lead) Member State of the PSUR single assessment procedure Austria Centrally authorised product(s) (CAP) Nationally authorised product(s) (NAP) NAP 14 The assigned procedure number should be included in the cover letter sent to EMA and NCAs. The format is: PSUSA/ /YYYYMM PSUSA: single assessment of PSURs Eight digit number: unique identification number YYYYMM:month and year of the DLP as published in the is usually revised on a monthly basis. Updates made to the when adopted by the CHMP and CMDh following consultation with the PRAC are highlighted in colour A comma separates the different active substances contained in a combination A slash indicates a single PSUR assessment covering the different substances and/or combinations of active substances 15 5

6 Active substances and combinations In case a specific salt, ester, etc. is mentioned in the list, PSURs only for this salt, ester etc. should be submitted. In all other cases the name of the active substance covers all salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives, as appropriate. If only the name of the acid or base specified, products containing salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of the acid or base are part of the single assessment procedure If a specific fixed combination medicinal product is not listed on the, the MAH should inform the Agency. 16 Timelines for PSUR submission: within 70 calendar days of the DLP (day 0) for PSURs covering intervals up to 12 months within 90 calendar days of the DLP (day 0) for PSURs covering intervals in excess of 12 months; If a single assessment is occurring for the first time, not all PSURs will cover the period indicated in the. In such cases, MAHs should cover in their PSURs the period between the DLP of the last PSUR that has been submitted (e.g. PSUR submitted at national level or as part of a PSUR Work-sharing procedure) and the DLP in the. 17 PSUSA Procedure Timelines 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 Day 120 Day 134 PRAC Rapporteur s / Member State updated assessment report (if necessary) PRAC recommendation adoption with the final PRAC assessment report CHMP opinion / CMDh position (in case PRAC recommends a variation, suspension or revocation of the MA) 18 6

7 The MAH is expected to provide, as applicable, by Day 90: Responses to the request for supplementary information from preliminary assessment report, Comment on the proposed wording (in case of a variation), Propose a wording in case the recommendation is a variation but no exact wording is proposed by the PRAC Rapporteur / Member State, provide a justification in case the MAH does not agree with the PRAC Rapporteur / Member State recommendation to vary, suspend or revoke the MA; and/or include additional comments or clarification deemed necessary by the MAH 19 In the case of any questions and requests regarding the : eurdlist@ema.europa.eu. 2/10/WC pdf

8 General issues Missing PSURs at Agency and nationally although PSUR required Unclear situation of legal status (known active substance / generic etc.) EMA statement: if a MAH cannot prove legal status, which justifies the non-submission of a PSUR, the PSUR has to be submitted. Disproportionate allocation of PSUR periods is in a constant change List should be checked for new / changed entries on a regular basis in order not to miss any PSUR submissions 22 General issues List is a living document, i.e. it can be amended whenever considered necessary by the PRAC, CHMP or CMDh in response to the emergence of relevant new safety information, newly authorised substances and requests received from the marketing authorisation holders as defined in [DIR Art 107c(6)]. Substances can be added, but also removed, as appropriate. At the moment the EURD does not include homeopathics and herbals (with the exception of some substances derived from plants hypericin etc.) In the case of any questions and requests regarding the EURD list: eurdlist@ema.europa.eu. 23 General issues The PSUR frequency and related data lock points for a given active substance or combination of active substances in the take effect six months after the publication date and overrule the submission schedule described in Article 107c (2) of Directive 2010/84/EU, and any conditions related to the frequency of submission of PSUR included in the marketing authorisation. Marketing-authorisation holders are requested to submit PSURs to national competent authorities or the Agency according to the dates published in the. 24 8

9 PSUR PBRER submission Transition period until 13 June 2016 For Centrally Authorised Products (CAPs): To the EMA: PSUR submission (in ectd format only) through esubmission Gateway/ Web Client including XML delivery file To the Rapporteur and all other Committee Members of the PRAC: follows CAP Dossier Requirements document for NCA submissions for countries not yet using the Common Repository 25 PSUR PBRER submission Transition period until 13 June 2016 For mixed CAP/NAP PSUSA procedure: To all Member States where authorised -(refer to Requirements for submissions for Periodic Safety Update Reports (PSUR) for MRP, DCP and National Products (NAPs)) To the PRAC Rapporteur if different from one of the Member States where the product is authorised To the European Medicines Agency submission (in ectd or NeeS format) through esubmission Gateway/ Web Client including XML delivery file created in the PSUR Repository user interface 26 PSUR PBRER submission Transition period until 13 June 2016 NAPs only PSUSA procedure: To all Member States in which the medicinal product has been authorised -(refer to Periodic Safety Update Reports (PSUR) for MRP, DCP and National Products (NAPs)) Lead Member State appointed for the procedure (if different from where the product is authorised) To the European Medicines Agency submission (in ectd or NeeS format) through esubmission Gateway/ Web Client including XML delivery file 27 9

10 PSUR PBRER submission Transition period until 13 June 2016 On 1 September 2015, the use of the XML delivery file for all PSUR submissions via the esubmission Gateway and/or the Web Client became mandatory. Therefore, it will no longer be possible to submit PSUR submissions using the existing file naming convention. The mandatory use of the PSUR XML delivery file is introduced to harmonise the submission mechanism for all PSURs and it will apply to all types of PSUR and PSUR supplementary information submissions For technical queries: ectd@ema.europa.eu 28 PSUR repository Article 25a of Reg. (EC) 726/2004 requires the Agency (+EC and MSs) to set up and maintain a repository for PSURs and corresponding assessment reports. Regulation (EC) No 726/2004, Directive 2001/83/EC and the Commission Implementing Regulation (EU) 520/2012: the PSUR Repository has to adequately support the following processes: a.the electronic submission of PSURs and PSUR assessment reports b.the storage and retrieval of PSURs and PSUR assessment reports by providing access, query and download functionalities by authorised users (NCAs, EMA, the Commission, PRAC, CHMP, CMDh) As per the Article 107b paragraph 1 and Article 28(2) regulation 726/2004) all PSUR procedures shall be submitted electronically. 29 PSUR repository For both EU-single assessment(psusa) and non-eu-single assessments, the single, purely national procedures, where the active substance is only authorisedin one Member State -- Secure electronic submission point for MAHs for PSUR submissions -- Common storage place for PSURs, PSUR Assessment Reports (ARs), comments and final outcomes 30 10

11 PSUR repository All MAHs, who have not previously used the esubmission Gateway / Web Client, should register via online registration form Guidance and Trainings on -- Strong recommendation to switch to the XML delivery file option at their next opportunity. -- Use a dedicated user interface for the creation of the Repository specific XML delivery file. -- Use guidance provided in Annex 3 of the PSUR filenames for repository submissions when using the XML approach. 31 PSUR repository Access to Repository: registration; user name and password to log into the repository using a web browser and navigate to There is no change to the existing submission rules for submissions to NCAs (national competent authority). Submission to PSUR Repository is recommended for all PSURs (also non pilot products/ supplementary information) 32 PSUR repository User interface for the creation of the Repository specific XML delivery file 33 11

12 PSUR repository Timetable: Go-live - 26 January 2015 Pilot - 26 January 2015 April/May 2015 Switch-on: until mandatory use Mandatory use: from 13 June Worksharing PSUR single assessment (PSUSA) for NAPs started at the end of 2014 for products with Data Lock Points (DLPs) falling on or after 1st September Establishment of single assessment for NAPs finalisation of outstanding Worksharing procedures Shortened procedures for old Worksharing If possible relocation of WS procedures to PSUSAs Link: 35 Renewals National requirements for PHV renewal documents: Generics for which PSURs are required according to the, need no addendum to the clinical overview Generics for which no PSURs are required according to the : -- AT=RMS: Addendum to the clinical overview is required -- AT=CMS: Addendum is not required if not otherwise decided by RMS -- Nationally approved: Addendum is required

13 PSMF New application: Only a submission of the PSMF summary is required. It has to include the following statement: proof for a qualified person responsible for pharmacovigilance; the Member States in which the qualified person resides and carriesout his/her tasks; the contact details of the qualifiedperson; a statement signed: applicant has the necessary means to fulfil the tasks and responsibilitieslisted in Title IX; a reference to the location where the pharmacovigilance system master file for the medicinal product is kept. 37 PSMF QPPV has to both reside and operate in the Union (+ NO, IS, FL) Details of keeping have to be entered in the Extended Medicinal Product Dictionary (XEVMPD), including changes All MAHs have to register Unique code will be assigned PSMF not part of the marketing authorisation(ma) dossier and is maintained independently from the MA It should be permanently available for inspection and should be provided within 7 days to the Competent Authorities if requested 38 PSMF Name and contact detailsof a QPPV and each changeof these data have to be reported to AGES and agency National authorisation: Change of a PSMF summaryhas to be done as variation type IA Timelines: at the latest until 02 July 2015 (for CAP) and 21 July 2015 (for all other registrations) a PSMF had to be submitted either in the frame of a renewalor as an extra submission 39 13

14 VIELEN DANK FÜR IHRE AUFMERKSAMKEIT Contents: Part I: Title page including signature Part II: Executive Summary Part III: Table of Contents 1. Introduction 2. Worldwide marketing authorisation status 3. Actions taken in the reporting interval for safety reasons 4. Changes to reference safety information 5. Estimated exposure and use patterns 6. Data in summary tabulations 7. Summaries of significant findings from clinical trials during the reporting interval Findings from non-interventional studies 9. Information from other clinical trials and sources 10. Non-clinical Data 11. Literature 12. Other periodic reports 13. Lack of efficacy in controlled clinical trials 14. Late-breaking information 15. Overview of signals: new, ongoing or closed 16. Signal and risk evaluation 17. Benefit evaluation 18. Integrated benefit-risk analysis for authorised indications 19. Conclusions and actions 20. Appendices to the PSUR 42 14