Dr. Irmgard Resch

Abteilung Begutachtung Pharmakovigilanz

PSUR, PSUSA und EURD-Liste - ein Update

AGES Gespräch 13.6.2017

As of 13 June 2016, all periodic safety update reports (PSURs) for human medicines authorised in the European Union (EU) must be submitted to the PSUR repository.

The PSUR repository provides an important simplification for marketing authorisation holders allowing them to send all PSURs to a single recipient.

all PSUR submissions across Europe only via this channel AGES: no paper, CD-, e-mail-, CESP-submissions accepted for PSURs

PSUR repository Mandatory

• Go-live - 26 January 2015 • Pilot - 26 January 2015 – 10 February 2016 • Switch-on: 11 February – 12 June 2016 • Mandatory use: since 13 June 2016

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eSubmission over Gateway / Web Client, MAH should register to use the submission tools, existing eSubmission Gateway/Web Client users do not need to re-register. Submissions are made using an XML delivery file. The delivery files are used to provide required metadata allowing the EMA to process the submissions. The XML delivery file must be included within the submission package (i.e. in the relevant ZIP file).

New: User Guidance for submissions via eSubmission Gateway / Web Client using xml delivery files, EMA/346582/2016, 5 May 2017

http://esubmission.ema.europa.eu/gateway/Gateway%20user%20guide%20xml%20delivery%20files.pdf

PSUR repository New information

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The PSUR submission should include a cover letter containing a completed formatted table template to facilitate the registration of the submission.

This template should be completed in accordance with the published EURD list, where the procedure number is the combination of a unique ID and the applicable Data Lock Point (DLP) in YYYYMM format.

PSUR submission Cover letter

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PSUR submission Formatted table template

1* Applicant/MAH Name

2* Customer Account Number xxxx (only for WS, IG and MAA)

3* Customer Reference / Purchase Order Number

4 INN / Active substance/ATC Code

5 Product Name of centrally authorised medicinal product(s)

5.1* Nationally Authorised Product(s) Please refer to Annex I

6* Product Number or

Procedure Number or

PSUSA (PSUR Single Assessment)

Non-EU single assessment

PSUR Period Covered (for both PSUSA and Non-EU procedures)

H XXXX or

EMEA/H/C/XXXX / type / or

PSUSA/000XXXXX/yyyymm

National Marketing Authorisation No

-

7* Submission Type (Please select)

7.1* Submission Unit Type

7.2* Grouping (more then one scope) Yes

7.3* Submission Description

8* Please provide the name(s) of any centrally authorised medicinal product for which the same change(s) are

being applied for outside of this procedure

Product name and number:

9* RMP included in this submission: Yes No RMP version N.

10* eCTD sequence 00xx Related sequence 00xx

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PSUR submission Formatted table template

11* Contact Persons’ details

(include email address)

A) Regarding the content of the submission:

B) Regarding eCTD technical questions:

To be completed as applicable:

12*

For PAM submissions or in case a

procedure such as a variation

addresses an outstanding PAM:

PAM type

PAM area

PAM data

PAM originating from:

(If this submission is related to a previous PAM, please specify previous PAM number)

Brief description of the PAM including number (if known) and refence to the procedure, date and Committee the PAM was requested:

EPITT Number (For SDA submissions only)

I confirm that the submission does not fall under any categories of the Classification guidance on variations and that the data

submitted do not influence the benefit-risk balance and therefore do not require taking further regulatory action on the marketing

authorisation.

I confirm that the submission does not include a final study report (except P46 applications)

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PSUR submission Formatted table template

13* For submissions of final study reports in the

context of a variation

14 For P46 submissions study title and number stand alone study(ies).

study title and number part of a clinical development program. The application

consisting of the full relevant data package (i.e. containing several studies) is expected to be

submitted by MM/YY. A line listing of all the concerned studies is attached for your

consideration.

15* Submission in accordance to Art. 8 of Paediatric

Regulation (EC) No 1901/2006 of 12/12/2006

Is your product is protected by a Supplementary Protection Certificate (SPC) or a patent that

qualifies for a SPC?

Yes No

16 Confirmation that the clinical reports submitted

for scientific evaluation are the same as those

submitted for publication, in the Redaction

Proposal and Final Redacted Versions, except for

the redactions

Included

Yes

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Medicinal products authorised under Articles 10(1), 10a, 14 or 16a of Directive 2001/83/EC are exempted from routine submission of PSURs unless otherwise specified in the MA or required through the EURD list. National competent authorities can also request PSURs for generic medicinal products at any time on the grounds detailed in Article 107c (2) of the Directive.

MAHs of such medicinal products should use alternative mechanisms (signal management etc.) to communicate relevant new safety information to regulatory authorities (see GVP module VI and IX).

PSUR submission Special cases

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If fixed dose combination not listed in the EURD list, PSURs submitted as specified in the conditions of the MA for the combination product (if any), or otherwise according to the standard submission cycle unless the combination medicinal product falls within the categories of medicinal products exempted from the obligation to submit PSURs.

MAHs should submit PSURs once a medicinal product is authorised in the EU, regardless of its marketing status.

PSUR submission Special cases

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Non-interventional PASS study protocols and reports should not be submitted to the PSUR Repository. The PASS 107 submissions should be submitted to EMA using eSubmission Gateway / Web Client using the relevant submission type. PASS 107 submissions for centrally authorised products are available to the NCAs via the Common Repository. For more information on the PASS 107 submissions please see EMA regulatory Post-Authorisation Guidance.

Link: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000090.jsp

PSUR submission Special cases

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If a parallel importer receives a notification of an adverse drug reaction from a patient, a doctor or any other source, the parallel importer should inform this person that the adverse drug reactions should be reported directly to the MAH of the medicinal product concerned. The parallel importer should also inform the MAH immediately.

Only MAHs are required to submit PSURs as per the provisions of Article 107b of Directive 2001/83/EC and Article 28(2) of Regulation (EC) No 726/2004. Parallel importers do not qualify as MAHs, and therefore they are not subject to the obligation to submit PSURs.

PSUR submission Special cases

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A risk management plan (RMP) update can be submitted with a PSUR for single centrally authorised medicinal product (CAP) or a mixture of CAPs belonging to the same global marketing authorisation when the changes to the RMP are a direct result of data presented in the PSUR. In this case no stand-alone RMP variation is necessary.

If the above does not apply, the updated RMP should be submitted as a stand-alone variation.

PSUR submission Additional RMP

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Literatur should not only be presented in the PSUR, but a comment / conclusion of the MAH on the benefit risk should be added

MAH should not only describe important case reports, but draw conclusions and justify them as well.

The Reference Safety Information (RSI) should be in English When the RSI is added, the MAH should make a statement (in

the regional part of the PSUR) if/that the information is available in the local SmPCs as well

Fatal cases which are mentioned in the signal section and are not commented, are trigger for questions by LMS

PSUR submission Hints on the quality of PSURs

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If you are experiencing issues with the XML delivery file screen, PSUR repository interface or eSubmission Gateway/Web Client, contact the EMA via https://servicedesk.ema.europa.eu/ This portal replaces gatewaysupport@ema.europa.eu eCTD@ema.europa.eu, PSURrepository@ema.europa.eu. PSUR submission for nationally authorised products: PSURquery@ema.europa.eu

PSUR repository Contacts

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For queries on fees and QPPV advice notes (please refer to question “What fee do I have to pay?”), you can contact the EMA using the designated EMA Fees Query Form available on the Pharmacovigilance fees: questions and answers webpage.

The Agency aims to respond to your query within 5 working days. Information whether query refers to NAP or CAP, the procedure number of the PSUSA, the name of the product and the name of the active substance/combination of active substances.

keep ‘Article 57 database’ updated (MA withdrawn etc.)

PSUR submission Fees

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In addition to the „active“ EURD list there is information available on removed entries:

EURD list Update

Active substances and combinations of active substances removed from the EURD list Month removed Comments

amyleine / chlorhexidine Apr 17 Entry to be removed since no products have been identified containing this active substance combination.

bacitracin / chlorhexidine Apr 17 Entry to be removed since no products have been identified containing this active substance combination.

bendroflumethiazide Apr 17 Removal from EURD list: New entry: "bendroflumethiazide, bendroflumethiazide / potassium chloride" to be followed (PSUSA/00010583)

benzalkonium chloride / chlorhexidine dihydrochloride / isopropyl myristate / paraffin liquid Apr 17 Entry to be removed from the EURD list since products in only one MS identified containing this combination of

active substances.

collagen Apr 17 Entry to be removed since no products have been identified containing this active substance combination.

collagenase clostridium histolyticum (all indications except for treatment of Dupuytren’s contracture and Peyronie’s disease) Apr 17 Entry to be removed since no products have been identified containing this active substance combination.

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For information on how to submit requests for amendments of the EURD list or any other questions related to the EURD list, please refer to the ‘Introductory cover note to the List of European Union reference dates and frequency of submission of Periodic Safety Update Reports (24 October 2016, EMA/606369/2012 Rev.15)

EURD list Further information

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History of pharmacovigilance system inspections Worldwide marketing approval status Actions taken for safety reasons during the period Significant changes to the SmPC Estimated exposure and used patterns Data in summary tabulations Summaries of significant safety and efficacy findings from

clinical trials and non-interventional studies during the period covered by the renewal

Literature Risk evaluation

Renewal ACO structure

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Benefit evaluation Benefit/risk balance Late-breaking information MAHs are advised to consider the GVP Module VII on PSURs as guidance for preparation of the ACO. Link: CMDh Best practice guide on the processing of renewals in the mutual recognition and decentralised procedures (CMDh/004/2005/Rev.14) http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/Renewal/CMDh_004_2005_Rev14_2016_02_clean.pdf

Renewal ACO structure

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The Clinical Expert should: Confirm that no new clinical data are available which change or result

in a new benefit-risk balance evaluation.

Confirm that the product can be safely renewed at the end of a 5-year period for an unlimited period.

Confirm that the authorities have been kept informed of any additional data significant for the assessment of the benefit-risk balance of the product concerned.

Confirm that the product information is up to date with the current scientific knowledge including the conclusions of the assessments and the recommendations made publicly available on the European medicines web-portal.

Renewal Addendum to Clinical Overview

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AT=RMS: ein „Addendum zum clinical overview“ ist vorzulegen. AT=CMS: ein „Addendum zum clinical overview“ ist vorerst nur vorzulegen, wenn es vom Reference Member State gefordert wird.

Nationally authorised products:

ACO required for all products (also generic, well established use, traditional herbal and homeopathic authorisations)

The “Addendum to the clinical overview “ should cover the period from the date of approval to the date of submission of the renewal.

Apothekeneigene Zulassungen so far exempted from PSUR submission.

Renewal ACO Requirements for AT

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Periodic safety update: questions and answers http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000041.jsp&mid=WC0b01ac0580023e7d further important links

eSubmission / PSUR repository http://esubmission.ema.europa.eu/psur/psur_repository.html

BASG Homepage Pharmakovigilanz FAQ http://www.basg.gv.at/pharmakovigilanz/faq-pharmakovigilanz/ Veterinary PSURs: Q&A: Periodic Safety Update Report http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000064.jsp

PSURs Further information

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Frage von Pharmig: Auf der BASG-Website werden unter eServices >> Zulassung und Lifecycle von Arzneispezialitäten >> Laufende Abringen nationale PSURs (Non-EU-SA), welche über das PSUR-Repository eingereicht werden, als „nationales PSUR Gutachten“ mit einer Verfahrensnummer angeführt. Wie lange dauert von Seiten der AGES der Eintrag auf dieser Seite? Oder anders gefragt: Ab welcher Dauer nach Einreichung und Nicht-Erscheinen in eServices/Laufende Anbringen kann man damit rechnen, dass die Einreichung/Übertragung möglicherweise nicht geklappt hat? Ab wann kann/soll man nachfragen?

Hintergrund: Eine Woche nach unserer Einreichung über das PSUR-Repository gibt es noch keinen Eintrag in den eServices.

PSUR submission Question

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Bearbeitung erfolgt meist innerhalb einer Woche bitte nachfragen, wenn nach einer Woche Bestätigung noch

nicht in eServices aufscheint E-Mail an: repository@ages.at Mögliche Fehlerquellen: -- falsches Land angeklickt durch MAH -- Häkchen vergessen durch AGES

PSUR submission eServices

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Vielen Dank

für die Aufmerksamkeit!

BASG - Bundesamt für Sicherheit im Gesundheitswesen

www.basg.gv.at

Traisengasse 5 1200 Wien

Gutachterin Pharmakovigilanz

T +43(0) 50555-36260

Irmgard.resch@ages.at

Mag. Dr. Irmgard Resch