Requirements for PSURs in accordance with Vol.9A of The Rules Governing Medicinal Products for Human Use and EMA's position

1. KONSTANTIN KACHULEV, MPharm
Drug safety specialist,
Pharmacovigilance

2. What is PSUR?
 Essentials:
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 (MAHs) in the light of new or changing
information at defined time points during the post-authorisation phase. The required format and content of PSURs in the EU
are based on those for the Periodic Benefit Risk Evaluation Report (PBRER) described in the ICH-E2C(R2) guideline. The PBRER
replaces the PSUR format previously described in the ICH-E2C(R1). In the EU, the report shall be described and named as PSUR [IR
Art 34 and 35].
 Time:
They are submitted regularly with periodicity established in Regulation
(EC) No 726/2004 and Directive 2001/83/EC
Time 6m 1y 1,5y 2y 3y 4y 7y
Authorisation
& Market
!!!NO MATTER IF IT IS MARKETED OR NOT MARKETED!!! YOU
SHALL SUBMIT!!!
 Where:
They should be submitted to the Competent Authorities of all Member
States and to the Agency if products are authorised through centralised
procedure, or only to the Competent Authorities if they are authorised
nationally

3. Format and contents of the PSUR
 The PSUR shall be based on all available data and shall focus on new information which has
emerged since the data lock point of the last PSUR. Cumulative information should be taken into
account when performing the overall safety evaluation and integrated benefit-risk assessment.
 Examples of sources of efficacy, effectiveness and safety information that may be used in the
preparation of PSURs include the following:
o non-clinical studies;
o spontaneous reports;
o active surveillance systems (e.g. sentinel sites);
o investigations of product quality;
o product usage data and drug utilisation information;
o clinical trials, including research in unauthorised indications or populations;
o observational studies, including registries;
o patient support programs;
o systematic reviews and meta-analysis;
o marketing authorisation holders sponsored websites;
o published scientific literature or abstracts, including information presented at scientific meetings;
o unpublished manuscripts made available to the marketing authorisation holder;
o licensing partners, other sponsors or academic institutions and research networks;
o competent authorities (worldwide) websites.

4. Format and contents of the PSUR
(CONTD)
 When preparing the PSUR, the ICH-E2C(R2) guideline on
PBRER should also be applied. When no relevant information is  8. Findings from non-interventional studies
available for any of the sections, this should be stated.  9. Information from other clinical trials and sources
 10. Non-clinical Data
 Part I: Title page including signature  11. Literature
 Part II: Executive Summary  12. Other periodic reports
 Part III: Table of Contents  13. Lack of efficacy in controlled clinical trials
 1. Introduction  14. Late-breaking information
 2. Worldwide marketing authorisation status  15. Overview of signals: new, ongoing or closed
 3. Actions taken in the reporting interval for safety reasons  16. Signal and risk evaluation
 4. Changes to reference safety information  16.1. Summaries of safety concerns
 5. Estimated exposure and use patterns  16.2. Signal evaluation
 5.1. Cumulative subject exposure in clinical trials  16.3. Evaluation of risks and new information
 5.2. Cumulative and interval patient exposure from marketing  16.4. Characterisation of risks
experience  16.5. Effectiveness of risk minimization (if applicable)
 6. Data in summary tabulations  17. Benefit evaluation
 6.1. Reference information  17.1. Important baseline efficacy and effectiveness information
 6.2. Cumulative summary tabulations of serious adverse events from  17.2. Newly identified information on efficacy and effectiveness
clinical trials  17.3. Characterisation of benefits
 6.3. Cumulative and interval summary tabulations from post-  18. Integrated benefit-risk analysis for authorised indications
marketing data sources
 18.1. Benefit-risk context – Medical need and important alternatives
 7. Summaries of significant findings from clinical trials during the
 18.2. Benefit-risk analysis evaluation
reporting interval
 19. Conclusions and actions
 7.1. Completed clinical trials
 20. Appendices to the PSUR
 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

5. Template for Cover Page for PSUR Submission
Title and product
Products hold by
MAH with the
same INN
Type of
authorisation
procedure
Dates
Covered Interval
MAH
Qualified Person
responsible for
PharmacoVigilance

6. General principles
 General scope – presentation, analysis and evaluation of new or changing safety data
received during period covered by the PSUR
 ONE PSUR – ONE MAH – All elements of the data for the product should be presented
in separate sections and included in a single PSUR
 Products authorised to more than one MAH – Where a product is authorised to more than
one Marketing Authorisation Holder, in the case of multiple applications, submission of
common PSURs is acceptable provided that the products remain identical in all respects
apart from their invented names and that the PSURs are submitted separately by each
MAH. Each MAH remains responsible for the appropriate submission of PSURs for their
products.
 Frequency of Review and Reporting*
 Reference Safety Information – an objective to a PSUR is to establish whether information
recorded during the reporting period is in accordance with previous knowledge of
the medicinal product safety, and to indicate whether changes should be made to
the Product Information or the Risk Management Plan. Reference information is
needed to carry out this comparison. It is common practice for MAHs to prepare their own
Company Core Data Sheet (CCDS), which includes material relating to safety,
indications, dosing, pharmacology and other information concerning the product. The
safety information contained within the CCDS is referred to as Company Core Safety
Information (CCSI).
 Presentation of Data on Individual Cases**

7. * Frequency of Review and Reporting
 Regular and Ad Hoc Submission of PSURs –
 Before initial placing on the EU Market:
 Immediately upon request from a Competent Authority or the Agency
 At least every 6 months after authorisation
 After initial placing on the EU Market:
 6-monthly PSUR submissions should be continued until 2 full years of
marketing experience in the EU has been gained;
 yearly PSURs for the following two years; and
 thereafter PSURs should be submitted at 3-yearly intervals;
 in addition, PSURs should be submitted immediately upon request
from a Competent Authority or, for centrally authorised products, from
the Agency
 The date of initial placing on the EU market is the date of launch, for the first time, in any Member State
 Each PSUR should cover the period of time since the last PSUR and should be submitted within 60 days after the data lock point.
 When yearly or 3-yearly PSURs are due for submission, multiple 6-monthly or yearly PSURs are acceptable, provided that the MAH
submits a PSUR Summary Bridging Report. It should be noted that in such cases, the MAH should not send 6-monthly or yearly
PSURs 60 days after the data lock points of these 6-monthly or yearly PSURs, but should send them only at the required due date
(yearly or 3-yearly).
 If a time gap occurs between the data lock point of a regular PSUR and a request from a Competent Authority (e.g. renewal, Risk-
Benefit Review, ad hoc PSUR request), a PSUR Addendum Report should also be submitted. For a PSUR that spans longer time
intervals, e.g. 3 years, an Addendum Report would only be considered appropriate if the time since preparation of the 3-year PSUR
and the locally required report is greater than 6 months.

8. * Frequency of Review and Reporting
(CONTD)
 Submission of Periodic Safety Update Reports for Renewal of Marketing Authorisations – The MAH should submit safety
data with the renewal application at least 6 months before the expiry date of the marketing authorisation in the EU
and lock the data no more than 60 days before submitting the PSUR. The data lock point for submission of safety
information should be at 4 years and 4 months following the marketing authorisation date. The MAH should submit the
PSUR, or the PSUR plus PSUR Addendum Report and a PSUR Summary Bridging Report, bridging all PSURs covering
the period of 4 years and 4 months. If the Competent Authority or the Agency concludes that an additional renewal is
needed (second one), this conclusion may include a requirement for an additional 6 months or 1 year report. The
second renewal application should discuss PSURs data covering a 5-year period since the data lock point of the PSUR(s)
submitted with the first renewal application.
 Circumstances Where the Periodicity May Be Amended – Where an amendment is proposed, the MAH or Applicant
should submit, as part of the application for a marketing authorisation, a reasoned request for the amendment,
which, if granted, becomes part of the conditions of authorisation. Such application follows the procedures for a type
II variation.
 Circumstances where less frequent submission of PSURs may be appropriate include:
 Products authorised through line-extensions to existing medicinal products;
 Newly authorised generic medicinal products.
 However, submission of PSURs at a lower frequency less than once every 3 year is not possible.
 Circumstances where more frequent PSUR submission may be required include:
 variations introducing new indications, populations, dosage forms and routs of administrations;
 an active substance which is a different salt/ester or derivative (with the same therapeutic moiety);
 the presence of an excipient without an established safety profile; and
 a Risk Management Plan in place for a corresponding originator product requiring specific monitoring of a safety concern.

9. * Frequency of Review and Reporting
(CONTD2)
 Preparation of Periodic Safety Update Report
according to the International Birth Dates –
 Medicinal products, which are also authorised outside the EU, will have an
International Birth Date (IBD).
 The IBD is the date of first marketing authorisation of a medicinal product
granted to the MAH anywhere in the world.
 For practical reasons, the IBD may be defined as the last day of the month
in which this first authorisation date falls.
 In order to harmonize PSUR submissions internationally, the MAH may use
the IBD to determine the dates of the data lock points for the PSUR
submission schedule, provided that the first data lock point falls within
the 6 months following the EBD.
 The IBD and EBD can be harmonized. It is difficult but feasible process
where the MAH and Competent Authorities may liaise and designate an
EU HBD which may be the IBD.

10. ** Presentation of Data on Individual Cases
*Medically unconfirmed reports should be provided as an annex to the PSUR as a line-listing
**Line- listing should be provided as an annex to the PSUR
***For the purpose of this Table, the term contractual partners does not refer to persons and organisations to
whom the MAH has transferred pharmacovigilance tasks and functions. Such persons and organisations are
included in “Direct Reports to MAH”

11. Model for a Periodic Safety Update Report (PSUR) I
 PSUR section “Executive Summary” – a brief overview of the PSUR which includes 1) MAH worldwide
status; 2) information related to the covered period; 3) exposure data; 4) number of new cases reported
and cumulative numbers; 5) other issues and safety concerns; 6) overall findings of the PSUR, and 7)
conclusions.
 PSUR section “Introduction” – brief introduction of the product.
 PSUR section “Worldwide Marketing Authorisation Status” – provides cumulative information. The
following information should be provided, as a table, for all countries. 1)dates for marketing
authorisation and subsequent renewal; 2) any qualifications surrounding the authorisation; 3) treatment
indications and special populations covered by the authorisation; 4) lack of approval, including
explanation by the authorities; 5) dates of launch; 6) dates for withdrawal, revocation or suspension of
the authorisation; 7) Invented name(s). If there are important differences for a same product in different
countries, which would reflect different types of patient exposure, such information should be noted.
 PSUR section “Update of Regulatory Authority or Marketing Authorisation Holder Actions
taken for Safety Reasons” - actions relating to safety that were taken during the period covered by the
PSUR and between data lock point and PSUR submission: 1) marketing authorisation withdrawal,
revocation or suspension; 2) failure to obtain a marketing authorisation renewal; 3) restrictions on
distribution; 4) clinical trial suspension; 5) dosage modification; 6) changes in target population or
indications; 7) formulation changes; 8) urgent safety restrictions.
 PSUR section “Changes to Reference Safety Information” – version of the CCDS with its CCSI.
When meaningful differences exist between the CCSI and the EU/Member State’s Summary of Product
Characteristics (SPC), a brief comment should be prepared from the MAH to describe the local
differences and their consequences on the overall safety evaluation.

12. Model for a Periodic Safety Update Report (PSUR) II
 PSUR section “Patient Exposure” – Estimating patient exposure data for marketed medicinal products often
relies on gross approximations of in-house or purchased sales data or volume to determine patient exposure.
When exposure data are based on information from a period that does not fully cover the period of the PSUR, the
MAH may extrapolate using the available data
 PSUR section “Presentation of Individual Case Histories” - This section should contain a description and
analysis of selected cases containing new or relevant safety information and grouped preferably by medically
relevant headings/MedDRA System Organ Classes (SOCs). If it is obtained subsequent information such a
follow-up data for the individual cases, it should be submitted with the next PSUR.
 A) “Cases Presented as Line-Listings” –
 All serious adverse reactions and non-serious unlisted adverse reactions from spontaneous reporting;
 All serious adverse reactions (attributable to the medicinal product by either investigator or sponsor) available from post-
authorisation safety studies (PASS) and other studies (including those which are part of the Risk Management Plan) or
named-patient/compassionate use;
 All serious adverse reactions, and non-serious unlisted adverse reactions from the literature;
 All serious adverse reactions transmitted to the Marketing Authorisation Holder by worldwide regulatory authorities.
 …in the form of an annex to the PSUR:
 All non-serious listed adverse reactions from spontaneous reporting;
 All serious and non-serious (listed and unlisted) adverse reactions reported by Patients/Consumers and other non-
healthcare professionals (not medically confirmed).
 The following headings are also included in this section:
 MAH case reference number
 Country in which the case occurred
 Source
 Age and sex of the patient etc.

13. Model for a Periodic Safety Update Report (PSUR) III
 B) “Cases Presented as Summary Tabulations” – for each of the line-listings
 C) “Marketing Authorisation Holder’s Analysis of Individual Case Histories” – brief comments on the data
concerning individual cases
 PSUR section “Studies” – all studies (non-clinical, clinical and epidemiological) yielding safety
information (this includes lack of efficacy data) with a potential impact on product information, studies
specifically planned, in progress and those published that address safety concerns should be included
with a discussion of any interim or final results.
 A) “Newly Analysed Studies” – containing important safety information and newly analysed
 B) “Targeted New Safety Studies” – new studies specifically planned or conducted to examine a safety concern
 C) “Published Studies” – reports in the scientific and medical literature
 D) “Other Studies” – any relevant information from the data collected by pregnancy exposure registries and a
discussion of the positive and negative experience
 PSUR section “Other information”
 A) “Efficacy-related Information” – products used in prevention or in treatment of serious or life-threatening
diseases or products used in healthy Consumers medically relevant lack of efficacy reports, which may represent a
significant hazard, should be described and explained
 B) “Late-breaking Information” – any important, new information received after the database was frozen for
review and report preparation may be presented in here
 C) “Risk Management Plan”
 D) “Risk-Benefit Analysis Report”
 PSUR section “Overall Safety Evaluation” – MAH provides a concise analysis of the presented data
 PSUR section “Conclusion” – addresses the overall risk-benefit balance
 Bridging and Addendum Reports are included in the Appendices

14. Issues addressed in discussions
with MAHs
1. What is a Periodic Safety Updated Report (PSUR)? Rev. Dec 2007
2. What is the difference between the International Birth Day (IBD) and the European Birth Day (EBD) of the
medicinal product? Rev. Dec 2007
3. What us a data lock point (DLP) and how shall I calculate the first data lock point? Rev. Dec 2007
4. When should PSUR be submitted if my medicinal product is authorised after 20 November 2005? Rev. Dec
2007
5. When should PSUR be submitted if my product was authorised before 20 November 2005? Rev. Dec 2007
6. How to calculate the PSUR cycle for my medicinal product? Rev. Dec 2007
7. Can the PSUR submission cycle be amended, in which circumstances? Rev. Dec 2007
8. Can the Data Lock Point (DLP), which was initially based on EBD change during the PSUR cycle?
9. How shall I present my PSUR? Rev. Jul 2009
10. What is a summary bridging report? In which case is it required? New Dec 2007
11. If the medicinal product is not marketed, is the MAH required to submit a PSUR? Rev. Dec 2007
12. How and to whom shall I submit my PSUR? Rev. May 2010
13. How will my PSUR submission be handled (timetable)? Rev. Dec 2007
14. In the view of the upcoming renewal application, how I shall manage my PSUR submission? Rev. Mar 2009
15. What is an addendum report? In which case is an addendum report required? New Dec 2007
16. In which case are line-listings and/or summary tabulations required? New Dec 2007

15. EMA’s POSITION
 What is a Periodic Safety Updated Report (PSUR)? Rev. Dec 2007
 PSUR is an update report, at defined time points after authorisation, of the worldwide
safety experience of a medicinal product.
 What is the difference between the International Birth Day (IBD) and the European Birth
Day (EBD) of the medicinal product? Rev. Dec 2007
 The European birth date (EBD) is defined as the date of the first marketing authorisation
granted in the EU for a medicinal product to the MAH.
 The International birth date (IBD) is defined as the date of the first marketing
authorisation for a medicinal product granted to the MAH in any country in the world. In
the case the medicinal product is first authorised in Europe, the EBD and the IBD are the
same.
 What is a data lock point (DLP) and how shall I calculate the first data lock point? Rev.
Dec 2007
 The data lock point (DLP) is defined as the cut-off date for data to be included in a PSUR.
It may be set according to the European birth date (EBD) or International birth date (IBD)
of the medicinal product. The MAH should in any case submit the PSUR no later than 60
days after the DLP. The 1st DLP should be exactly 6 months after the date of Commission
Decision granting the Marketing Authorisation

16. EMA’s POSITION (CONTD)
 When should PSUR be submitted if my medicinal product is authorised
after 20 November 2005? Rev. Dec 2007
 After authorisation until the initial placing on the EU market
 At least every 6 months after authorisation
 After the initial placing on the EU market (date of launch in any
Member State)
 6-monthly PSUR submissions should be continued until 2 years marketing
experience in the EU has been gained
 Yearly PSURs for the following 2 years
 At 3-yearly intervals thereafter
 When should PSUR be submitted if my product was authorised before
20 November 2005? Rev. Dec 2007
 For marketing authorizations that will be renewed within three years of 20 November 2005 the next PSUR should be
submitted with the renewal application, unless otherwise agreed with the EMA/CHMP/CVMP. Thereafter, PSURs should
be submitted every three years, unless other requirements have been laid down as a condition of the marketing
authorisation.
 For marketing authorizations where the next renewal is more than three years from 20 November 2005, a PSUR should be
submitted within three years i.e. before 20 November 2008. The precise date of submission of the next PSUR should be
agreed with the EMA/CHMP/CVMP. Thereafter, PSURs should be submitted every three years, unless other requirements
have been laid down as a condition of the marketing authorisation.

17. EMA’s POSITION (CONTD2)
• How to calculate the PSUR cycle
After the initial placing on the EU Market
EU Serial No Date of submission
Period covered
for my medicinal product? Rev. From To
Dec 2007 3rd DLP + 1 day
4th DLP = 3rd DLP + 6
4th DLP + 60 days
#4 (6-monthly) months
Before the initial placing on the EU (13 Nov 2008) (12 Jul 2009)
(12 May 2009)
Market
EU Serial No Date of submission
Period covered
From To 5th DLP = 4th DLP + 6
4th DLP + 1 day 5th DLP + 60 days
1st DLP minus 6 #5 (6-monthly) months
1st DLP 1st DLP + 60 days (13 May 2009) (12 Jan 2010)
#1 (6-monthly) months (12 Nov 2009)
(12 Nov 2007) (12 Jan 2008)
(12 May 2007)
2nd DLP = 1st DLP 6th DLP = 5th DLP + 6
1st DLP + 1 day 2nd DLP + 60 days 5th DLP + 1 day 6th DLP + 60 days
#2 (6-monthly) + 6 months #6 (6-monthly) months
(13 Nov 2007) (12 Jul 2008) (13 Nov 2009) (12 Jul 2010)
(12 May 2008) (12 May 2010)
3rd DLP = 2nd DLP
2nd DLP + 1 day 3rd DLP + 60 days
#3 (6-monthly) + 6 months 7th DLP = 6th DLP + 6
(13 May 2008) (12 Jan 2009) 6th DLP + 1 day 7th DLP + 60 days
(12 Nov 2008) #7 (6-monthly) months
Initial placing on the market on date 3rd DLP + 4 months (12 Mar 2009) (13 May 2010) (12 Jan 2011)
(12 Nov 2010)
8th DLP = 7th DLP + 6
7th DLP + 1 day 8th DLP + 60 days
#8 (6-monthly) months
(13 Nov 2010) (12 Jul 2011)
(12 May 2011)
Before placing on the market  #9 (1 yearly)
8th DLP + 1 day
(13 May 2011)
9th DLP = 8th DLP + 1 year
(12 May 2012)
9th DLP + 60 days
(12 Jul 2012)
9th DLP + 1 day 10th DLP = 8th DLP + 1 year 10th DLP + 60 days
#10 (1 yearly)
(13 May 2012) (12 May 2013) (12 Jul 2013)
After placing on the market  10th DLP + 1 day
11th DLP = 9th DLP + 3
11th DLP + 60 days
#11 (3 yearly) years
(13 May 2013) (12 Jul 2016)
(12 May 2016)

18. EMA’s POSITION (CONTD3)
 Can the PSUR submission cycle be amended, in which circumstances? Rev. Dec
2007
 There may be circumstances where an amendment to the normal submission
cycle of PSURs is proposed by the MAH or requested by the CHMP for a given
medicinal product at the time of authorisation or post-authorisation.
 Can the Data Lock Point (DLP), which was initially based on EBD change during
the PSUR cycle?
 In order to allow synchronization of all PSUR submissions to regulatory
authorities worldwide, the MAH can request that the submission of PSURs is
based on the IBD instead of the EBD. As this would lead to a shift in the DLP, an
addendum report should be submitted in order to cover the period between the
last DLP and the new DLP.
 How shall I present my PSUR? Rev. Jul 2009
 A single PSUR is recommended for products containing one active substance
authorised to one MAH, which includes information on all indications, dosage
forms and regimens, with a single data lock Point (DLP) common for all aspects
of products use. The content and format of PSURs should be in accordance
with ICH Guideline E2C and its addendum and Volume 9a of the Notice to
Applicants.

19. EMA’s POSITION (CONTD4)
 What is a summary bridging report? In which case is it required? New Dec 2007
 The summary bridging report is a concise document integrating the
information presented in two or more PSURs to cover a specified period over
which a single report is requested (e.g. 2 consecutive 6-monthly reports for a
yearly PSUR, 6 consecutive 6-monthly PSURs, or a combination of 6-monthly
and yearly PSURs to make up a 3 year report).
 If the medicinal product is not marketed, is the MAH required to submit a
PSUR? Rev. Dec 2007
 The MAH is required to submit PSURs once a medicinal product is authorised
in the EU, even if it is not marketed.
 How and to whom shall I submit my PSUR? Rev. May 2010
 PSURs should be addressed and sent to national agencies and also to the
European Medicines Agency to the attention of the Product and Application
Business Support (PA-BUS) at the following address:
Product and Application Business Support (PA-BUS)
FAO PACs-DBM
European Medicines Agency
Loading Dock
Ontario Way
Canary Wharf
UK - LONDON, E14 4HB

20. EMA’s POSITION (CONTD5)
 How will my PSUR submission be handled (timetable)? Rev. Dec 2007
 Upon validation of a PSUR submission, the following 60-day timetable
shall apply to the PSUR evaluation:
DAY ACTION
Day 0 (CPMP meeting after validation) Start of the procedure
Day 30 Rapporteur’s preliminary assessment report
Day 40 CHMP Members’s comments
Day 50 Rapporteur’s updated assessment report (if necessary)
Day 60 CHMP adoption of conclusion
The submission deadlines and full procedural detailed timetables are now published as a generic calendar on the EMA
website (see: Submission deadlines and full procedural timetables).
 In the view of the upcoming renewal application, how I shall manage my
PSUR submission? Rev. Mar 2009
 A Periodic Safety Update Report (PSUR) shall be submitted as part of
the renewal application, at least 6 months before the expiry date of the
Marketing Authorisation (MA).

21. EMA’s POSITION (CONTD6)
 What is an addendum report? In which case is an addendum
report required? New Dec 2007
 An addendum report is an update to the most recently completed
PSUR, when a requested or required report covers data that fall
outside the defined period.
 In which case are line-listings and/or summary tabulations
required? New Dec 2007
 In case interval data, which fall outside a defined PSUR period, are
required to synchronize IBD/EBD, line-listings and/or summary
tabulations may be used instead of addendum reports.
 These are required when the additional period is less than 3 months
for a 6-monthly or a yearly PSUR, or 6 months for a longer-interval
PSUR, have elapsed since the DLP of the most recent PSUR.

22. Thank you!