The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Bluefish Pharmaceuticals.

1. General principles
of Periodic Safety
Update Reports
(PSUR)
2014-09-26
Dr. Julia Appelskog
EU QPPV
Head of Pharmacovigilance
Bluefish Pharmaceuticals
2014-09-26

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Disclaimer
 The views and opinions expressed in the following PowerPoint slides are
those of the individual presenter and should not be attributed to Bluefish
Pharmaceuticals.
 These PowerPoint slides are the intellectual property of the individual
presenter and are protected under the copyright laws. Used by permission.
All rights reserved.
2014-09-26

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Abbreviation
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 Decentralised procedure
EMA European Medicines Agency
MA Marketing Authorisation
MAH Marketing authorisation holder
MA Member State
MRP MRP: Mutual Recognition procedure
NAP Nationally Authorised Product (in the frame of this presentation includes
also DCP/MRP)
PRAC Pharmacovigilance Risk Assessment Committee
PSUR Periodic Safety Update Report
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Agenda
1 History of the PSUR
2 PSUR preparation
3 PSUR submission: Outcome of the
transitioning to the new system
4 PSUR Assessment
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Purpose of the Periodic Report
 PSURs as benefit risk decision-making tool
 The main purpose of PSUR is to present a comprehensive, concise, and
critical analysis of new or emerging information on the risks of the medicinal
product
 To consider whether any action concerning the MA for the medicinal
product is necessary
 Relates safety data to patient exposure
 Consider changes to product information to optimise product use
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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)
2012-2013
GVP Module VII –
PERIODIC SAFETY
UPDATE REPORT
1992
CIOMS II Guideline on PSURs
published
History of the PSUR
2014?
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Spirit of the legislation
New legal requirements for PSURs:
 Risk-based and proportionate approach
 Central repository
 PSUR single assessment: strengthens the Community system instead of
fragmented approaches on a national level
 Extended preparation and submission deadlines
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Old legislation
PSUR
RMP PSUR RMP PSUR
New legislation
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Relief for well-known products
Article 10(1)
Generic products
Article 10a
Well established
use products
Article 14
Homeopathic
medicines
Article 16
Traditional herbal
medicines
The legislation waives the obligation to
submit PSURs routinely (unless there is a
condition in the MA or requested by a CA):
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Implementation
 July 2012
- New format and content of PSUR + PRAC involvement in CAPs
 1 April 2013
- EURD list binding => PSUSA procedure involving PRAC implemented
for CAPs and NAPs containing the same active substance or
combination of active substances
-
 31st of August 2014
- Establishing of PSUR single assessment for NAP
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EURD list
 EURD = EU reference date list for PSUR submissions
 Harmonisation of DLP and frequency of PSUR submission for products
authorised in several Member States
 Periodicity defined on a risk-based approach
 Increase of predictability in terms of PSUR submission
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EURD list
 Monthly updated by EMA (Updates published at end of each month with
changes highlighted in colour)
- Outcomes of procedures (e.g. referrals, safety variations, extension of
indication, renewal, PSUR assessments that result in change in DLP,
PSUR frequency)
- Authorisation of a new substance
- Harmonisation of DLP with IBD
 The revised EURD List is adopted by the CHMP/CMDh after consultation of
the PRAC
 Any change to the dates of submission and frequency takes effect 6 months
after the publication date
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PSUR Work Sharing
 During the transition period until single assessment is established some
active substances for NAPs have been temporarily removed from the EURD
and have been included in the ‘List of Substances under PSUR Work
Sharing Scheme and Other Substances contained in Nationally Authorised
Products with DLP Synchronised’.
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New PSUR services
 Changes to EMA organisation announced 26
March 2014
 Revised operations for PSURs
 New roles:
- Procedure Manager (PM) - oversees all
aspects of the management of procedure
(main contact).
- Procedure assistant (PA)
- Specialised input from risk management
specialist, or regulatory affairs as needed.
 Allocation of PM and PA well in advance of
submission
 Pre-submission queries:
PSURquery@ema.europa.eu
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PSUR preparation
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New PSUR
 Structure
- PSUR structure defined by law and includes a scientific evaluation of the
benefit-risk balance
- Regulation 520/2012, GVP Module VII, ICH E2C(R2) provide the
guideline on the format and structure
- Line listings no longer required
 Benefit evaluation
- Important efficacy-effectiveness information
- Newly identified efficacy-effectiveness information
 Integrated benefit-risk analysis
- Importance of benefits and risks
- Discussion of the benefit-risk balance
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Format
 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
 5.1. Cumulative subject exposure in clinical trials
 5.2. Cumulative and interval patient exposure from
marketing experience
 6. Data in summary tabulations
 6.1. Reference information
 6.2. Cumulative summary tabulations of serious adverse
events from clinical trials
 6.3. Cumulative and interval summary tabulations from
post-marketing data sources
 7. Summaries of significant findings from clinical trials
during the reporting interval
 7.1. Completed clinical trials
 7.2. Ongoing clinical trials
 7.3. Long-term follow-up
 7.4. Other therapeutic use of medicinal product
 7.5. New safety data related to fixed combination
therapies
 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 on signals: New, ongoing or closed
 16. Signal and risk evaluation
 16.1. Summaries of safety concerns
 16.2. Signal evaluation
 16.3. Evaluation of risks and new information
 16.4. Characterisation of risks
 16.5. Effectiveness of risk minimisation (if applicable)
 17. Benefit evaluation
 17.1. Important baseline efficacy and effectiveness
information
 17.2. Newly identified information on efficacy and
effectiveness
 17.3. Characterisation of benefits
 18. Integrated benefit-risk analysis for authorised
indications
 18.1. Benefit-risk context — Medical need and
important alternatives
 18.2. Benefit-risk analysis evaluation
 19. Conclusions and actions
 20. Appendices to the periodic safety update report2014-09-26

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General principles
 All relevant safety information
- non-clinical studies;
- clinical trials, including research in unapproved indications or populations;
- spontaneous reports (for example, on the MAH’s safety database);
- MAH-sponsored websites
- product usage data and drug utilization information;
- published scientific literature or reports from abstracts including information presented at
scientific meetings; unpublished manuscripts;
- observational studies such as registries; active surveillance systems; systematic reviews
and meta-analyses;
- information arising from licensing partners, other sponsors or academic
institutions/research networks; patient support programmes;
- investigations of product quality;
- information from regulatory authorities.
 Worldwide market authorization status
- Should be by date so that the reader can follow the issues
(frequently ordered alphabetically by country)
 Update on Regulatory or MAH actions taken for safety reasons
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General principles
 One report for one active substance
- Separate section for data relating to particular indication, dosage form, route of
administration, dosing regimen, patient population (eg paediatric use)
 Separate PSUR in exceptional cases
 Fixed combination:
- Separate PSUR with cross reference to PSUR for each substance
 Joint PSURs possible (>1 MAH)
 Each MAH responsible for PSUR
- Companies must share information
- Specify in the Agreement who is responsible
 In-Licensed products
- Either submit licensor's PSUR report OR
- Submit own (refer to licensors report or include licensor's data)
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Industry experience
Multiple request from CA to present data in “old style” PSUR format
 Requests to include full narratives and CIOMS I forms
 Requests presentation of cases by listedness
 Requests for more details on individual cases rather than summary
 Inclusion of line listings of all fatal cases
 Requests for different presentations of data:
- HCP and consumer reports by SOC;
- Data presented by source, seriousness, listedness, medically confirmed etc.
Clinical Trial Information
- Requests to use the PSUR as a tool to update recruitment status of studies.
- Requests to provide a complete overview of all CTs
 Signals
- Requests for cumulative signal data in the Table in Section 15
2
0
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Procedural Issues
Challenges with timelines
-6 month PSURs overlap with Preliminary AR from previous PSUR,
expectation of MAH to complete AR process and next PSUR at the same time
-Final PRAC assessment report is not always received in time to incorporate
the comments into the next PSUR
-Short timeframe (changes to SmPC required within short time frames).
MAH Engagement
-Perceived lack of EMA contact for questions within tight timeframes
-Lack of direct contact with PRAC Rapporteur for any clarifications required
-Limited Opportunity for MAH interaction - day 90, PAR only. Opportunity to
appeal a decision?
2
1
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PSUR SUBMISSION
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PSUR submission
 According to the EU reference dates list
- The list overrules any PSUR requirements laid down in the MA
 According to a condition of the MA or
 According to Art 107c (2) of Directive 2001/83/EC and Art 28 (2) of
Regulation (EC) N. 726/2004:
- Every 6 months during the first 2 years
- One a year for the following 2 years
- Three-yearly intervals thereafter
 PSURs also need to be submitted upon request from a CA
“If substance not in the list : follow the submission frequency as per condition
in the MA if any, otherwise, follow the standard submission schedule”
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Pre-submission phase
 Extended pre-submission phase to prepare submission with MAHs.
 Notification to be sent to MAHs identified as part of the PSUSA in advance
of the submission date (advice note will be sent ca. 2 month prior to
submission date)
 Advice note will include information such as:
- Procedure number
- Submission deadline
- Lead PRAC Rapporteur
- Submission requirements
- Line listing of authorised products
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Pre-submission phase
 Consolidation of submissions in the MS and/or Agency
- Experience shows that there is a need to consolidate submissions at
MS-level prior to start of PSUSA
 After successful audit of PSUR repository, MAHs may still submit only to
MS for 12 more months
 Introduction of a 10 working days delay between submission and start for
PSUSAs containing NAPs (for MS reconciliation)
 Consolidated package will be made available to lead Rapporteur at start of
procedure
 New terminology: “PSUSA cut-off date”.
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To whom shall you submit PSUR?
CAPs
• PSURs to be submitted to:
• The EMA
• The Rapporteur appointed for
the procedure
• All other Committee Members
of the PRAC.
NAPs* involved in
a PSUSA
• PSURs to be submitted to:
• All Member States in which the
medicinal product has been
authorised
• The EMA
• The PRAC Rapporteur
appointed for the procedure.
Note: The term Nationally Authorised Product is intended to encompass medicines
authorised through MRP and DCP and purely nationally authorised products where
authorised in more than one Member State.
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Requirements of the (Co-) Rapporteurs and other Committee members
 http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guidelin
e/2009/10/WC500003980.pdf
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Current situation
 Different formats of PSUR submissions in the MS for NAPs:
- eCTD
- NeeS
- Paper
 Different extent of use of CESP
 PSUR within eCTD product lifecycle in most MS preferred
 PSUR submissions mostly stored within product related repository
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Current situation
Submission requirements % NCA
Submissions through CESP can be used (optional) 58%
A signed copy of the cover letter should be provided in paper
together with the CD/DVD (wet signature)
55%
A copy of the cover letter should be provided in paper with the
CD/DVD (no wet signature needed)
26%
The eCTD or NeeS must include a scanned copy of the signed
Cover Letter
39%
Email/EudraLink is accepted instead of the CD/DVD
(Max 80 MB)
23%
National portal can be used (optional) - see NCA website. 3 % (UK)
National portal must be used - see NCA website. 3% (ES)
Electronic signatures are accepted 19%
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PSUR submissions
E-Mail
Eudralink
Post
CESP
EudraVigilance
PRAC Recommendations
PSUR PSUSA
PSUR Repository
Current From Q1 2015
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PSUR repository
 Legal requirement for EMA to set up a PSUR repository (Article 25a of
Regulation (EC) 726/2004 as amended:
- The Agency shall, in collaboration with the national competent authorities and the
Commission, set up and maintain a repository for periodic safety update reports (hereinafter
the “repository”) and the corresponding assessment reports so that they are fully and
permanently accessible to the Commission, the national competent authorities, the PRAC,
the Committee for Medicinal Products for Human Use and the coordination group referred to
in Article 27 of Directive 2001/83/EC.
 A common storage place for:
- PSUR
- PSUR assessment reports
- PRAC recommendations
 Advantages:
- Centralised PSUR reporting
- Enhance access to data and information
- Fast benefit risk assessments of medicines.
PRAC Recommendations
PSUR PSUSA
MAH 1 MAH 2 MAH 3 MAH 4
CA 1 CA 2 CA 3 CA 4
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PSUR Repository
Legal References
Regulation (EC) 726/2004 as
amended
- Article 25a
- Article 28 paragraph 3
Directive 2001/83/EC as
amended
- Article 107b paragraph 2
- Article 107b paragraph 1
Requirements
 Accessibility of documents
 Allow search and queries
 Possibility to export the information
 Performances requirements (speed,
scalability)
 Allows unique identification
 Submission of documents
 Allow validation and quality monitoring
 Download functionality
 Storage capacity requirements:
- To store and archive a significant amount of
documents and the different versions
- The number of individuals PSURs received
per year is estimated to be 10,000
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Documents to be stored in the repository
 MAH cover letter
 PSUR
 Timetable for PSURs related procedure
 PSURs Assessment Reports
 Final assessment conclusions
 Comments on PSURs Assessment Report
 ICSRs Line Listing from the EudraVigilance Database
 Summary Tabulations from the EudraVigilance Database
 PRAC Recommendations following adoption of the Assessment Report
 Coordination Group Position and detailed explanation on scientific grounds for the
differences to PRAC recommendations
1. CHMP opinion
2. Detailed explanation on scientific grounds for the differences to PRAC recommendations
 Commission Decision
 Update to the Product Information related to the procedure
 List of Union Reference Dates and Frequencies of PSURs submission
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Access to the PSUR Repository
 European Commission
 National Competent Authorities
 PRAC Members
 CHMP Members
 Coordination Group Members
 EMA Secretariat
 MAHs
- Restricted access to MAH will simplify the process. This capability will be considered
based on a cost-implication analysis. If access cannot be granted, the EMA will provide the
MAH with the relevant documents via alternative methods (e.g. email or web posting).
 The General Public.
- Final assessment conclusions, recommendations, opinions and decisions will be made
publicly available by means of the European medicines web-portal. Technical links may
have to be established between the PSUR repository and the web-portal.
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Legal
requirement
Q1-Q2 2014
Definition of user
requirements
Q4 Pilot
phase with
MAHs
Available in
Q1 2015
PSUR Repository
PSUR Repository planned to be available in Q1 2015 and compulsory in 2016
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PSUR ASSESSMENT
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PSUR single assessment (PSUSA)
Started
in July
2012
CAPs
Started in
April 2013
(EURD list
entered into
force)
CAPs
+
NAPs
DLP
after 31st
August
2014
NAPs
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Assessment report
 A unique version of the AR is sent to all MAHs that submitted as part of a
PSUSA.
 The EMA is redacting the documents by deleting confidential commercial
information and patient personal data (PPD) in accordance with the criteria
described in the HMA/EMA document on handling requests for access to
PSURs applied (EMEA/743133/2009).
 A disclaimer is included in the EURD list:
- “Single Assessment Reports of PSURs are shared among all Marketing
Authorisation Holders involved in the concerned procedure.”
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Recommendations on the handling of access to PSURs
 EMEA/743133/2009. Access to PSURs has to be
only reactive and on request
 The minimum personal data to be deleted to ensure
anonymisation of the information would require the
deletion of information on:
- Date of birth, (Reporting) country, Patient
identification code
 “Commercially confidential information” is generally
considered to fall broadly into two categories:
- Confidential intellectual property, “know-how”,
and trade secrets (including e.g. formulas,
programs, process or information contained or
embodied in a product, unpublished aspects of
trade marks, patents, etc).
- Commercial confidences (e.g. structures and
development plans of a company).
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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)
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Day 90
 The MAH is expected to provide, as applicable, by Day 90:
- responses to the “request for supplementary information” as outlined in the
relevant section of the PRAC Rapporteur / Member State PSUR preliminary
assessment report,
- comment on the proposed wording (in case the recommendation is 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.
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Deviation from Principles of EU Legislation and ICH E2C
Inconsistent requests and interpretation by Assessors
- Lack of clarity regarding how assessors review signals and conclude on the data
- Expectation that old style PSUR will be followed re reviews
- Wide range of difference in experience and quality of Assessment Reports
Lack of understanding of the Global Nature of the PSUR/ PBRER
- Global implications of changing the EURD date/impact on submission outside
the EU
- Specific indication requests for Europe – this results in multiple and duplicated
work when annual PSUR/PBRER is not accepted in place of a six monthly report
( deviation from international harmonisation principles)
- Question in an AR: “What does PBRER stand for?”
4
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PSUR assessment
SCOPE
 Strengthening Collaborations for
Operating Pharmacovigilance in
Europe http://www.scopejointaction.eu/
Delivering tools for regulators
- “best practice”,
recommendations, guidance
based on successful
implementations
- Training (such as for PSUR
assessment)
WP 8 – Lifecycle PV
1. Identification of available data
sources outside spontaneous
reporting – lead: AIFA
2. Risk Management Plan assessments
– lead: NOMA
3. Post Authorisation Safety (and
Efficacy) Studies protcols and study
reports – lead: MPA
4. Benefit/risk assessment in the context
of PSUR and referral procedures -
lead: AIFA
5. Competency – lead: AIFA
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SCOPE WP 8
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Regulatory actions following assessment report
Maintenance of the MA
Suspension of the MA
Revocation of the MA
Variation of the MA
- new contraindication
- restriction of the indication
- reduction of the recommended dose
- SmPC/PL update (mainly changes to section 4.4 and 4.8 of the SmPC)
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Maintenance of the MA
 No change to Product Information/ Conditions of MA
 Request for cumulative review
 RMP update
 Amendment of the EURD list:
- frequency of PSUR
- separate/single PSUR per indication, pharmaceutical form, fixed-dose
combination
 Example from Jul 2014 PRAC meeting: Abatacept – ORENCIA
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8th Stakeholder meeting
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PSUR fee
 REGULATION (EU) No 658/2014 OF THE EUROPEAN PARLIAMENT AND OF THE
COUNCIL of 15 May 2014 on fees payable to the European Medicines Agency for the
conduct of pharmacovigilance activities in respect of medicinal products for human use
 From 26th of August 2014 the Agency charges procedure-based fees for the single assessment
of PSURs
- The fee for the assessment of PSUR is EUR 19 500 per procedure
 For the PSUR assessment under a PSUSA procedure involving more than one MAH, the total
amount of the fee will be divided among all the MAHs concerned proportionately to the number
of chargeable units.
 The MAH concerned will be established on the basis of the obligation to submit the PSUR(s)
and not on the basis of the actual PSUR submission(s) received by the EMA.
 The total of chargeable units in the procedure will be identified from the Art. 57 database.
 An advice note will be sent 3 months prior to the start date to the relevant QPPVs
 The invoice will be sent to each MAH with the relevant chargeable units calculation. The fee will
be due to the EMA within 30 calendar days.
 Reduced fee for an SME (i.e. micro-, small- or medium-sized enterprise) companies
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Common inspection findings
 Non-submission
- Complete non-submission of PSURs
- Submission the correct time frames
 Poor quality reports
- Incorrect format of the document
- New safety signals not or poorly assessed
- Medication error not highlighted
- Absence of use of standardized medical terminology (e.g. MedDRA)
- Published literature is not properly reviewed
- No conclusion drawn
 Omission of required information
- Update of Regulatory or MAH Actions taken for Safety Reasons
- Changes to Reference Safety Information
- Patient Exposure (poorly calculated, explanation of calculation is missing)
 Previous requests from Competent Authorities not addressed (e.g. close
monitoring of specific safety issues)
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Conclusions
Where we are?
 Still in learning phase
 Gained experience with CAP and mixed
single assessments for CAPs and NAPs
- Harmonization and efficiency
- Rapid update of product information
- Areas for clarification
 Room for improvement
 Transparency
What is next?
 PSUR single assessment for NAP (PSUSAs)
 PSUR repository
 Planned update of the PSUR template
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51. 2014-09-26