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

1. Road towards GVP VII: PSUR
(Rev 2) update
Dr. Rohith K Nair
Updates from PSUR explanatory notes

2. Disclaimer
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Used by permission. All rights reserved.

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. 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. 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. 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. 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. 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. 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. 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

11. PSUR PREPARATION

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. 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. Table of Contents

15. Table of Contents

16. Table of Contents

17. PSUR Submissions
MAH
CA

18. Conditions for PSUR submissions

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. 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. 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. Total PSUR submissions

23. PSUR Assessments

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. 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. Steps of assessment

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. 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. 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. 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. 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. 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. 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. • 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. 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. 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. 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. 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. 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. 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. 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.

43. References
• http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_g
uideline/2013/04/WC500142468.pdf
• http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_g
uideline/2017/04/WC500225264.pdf
• http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_event
s/events/2017/08/event_detail_001502.jsp&mid=WC0b01ac058004d5c3
• https://www.slideshare.net/Lszlrvai/psur-48378544
• https://www.slideshare.net/RohithKNair/periodic-safety-update-report-
psur
• http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_event
s/events/2017/08/event_detail_001501.jsp&mid=WC0b01ac058004d5c3