Periodic Safety

Update Report
(PSUR)

Nidhi Saxena
Xcellon Institute
 Introduction

Document that allows a periodic,
comprehensive assessment of the worldwide
safety data of a marketed drug or biological
product.

Concept evolved from the CIOMS Working
Group II report in 1992.

Formed the basis for ICH-E2C guidance for the
industry
− Defined the format and content for PSURs
− Introduced the concept of an international birth date
− Set the period for review of interval safety data as 6
months.
 Purpose

To evaluate to show whether a product's safety profile
has remained the same of has undergone changes

Changes should be made to product information to
optimise the use of a product

Rare adverse drug reactions can be easily identified

As the drug become available for indefinite use,
delayed onset ADRs become easier to identify.
 PSUR- General Principles

One report for the products containing one active
substances authorized to one marketing
authorization holder (MAH)

PSUR should cover all dosage forms, formulation and
indication

Separate presentation of data for different dosage
forms or populations if appropriate

Products authorized to more than one MAH

Each MAH is responsible for submitting PSURs even if
different companies market the same product in the
same country.

When companies are involved in contractual
relationships arrangements for sharing safety
information should be clearly set out.
 General Principles-Cont....


Combination Products

Safety information may be done as a separate
PSUR or included as separate presentations in the
report for one of the separate components with
cross-referencing.
 General Scope of information:

The report should present data for the interval of the
PSUR only except for regulatory status information,
renewals and serious unlisted ADRs, which should be
cumulative.

Report should focus on ADRs.

All spontaneous reports should be assumed be
reactions.

Reports should be from health care professionals.

Lack of efficacy reports should not be included in the
tables but should be discussed in the “other
information” section.
 Preparation of PSURs According to
the IBD
• International Birth Date (IBD)
– Date of the first marketing authorization for the
product granted to any company in any country
in the world.
– Each medicinal product should have IBD
– This date should be synchronized around the
world for PSUR reporting such that all
authorities receive reports every 6 months or
multiple of six months based on IBD.
 Frequency of Reporting
• PSUR should cover the period since the last update
report
• submitted within 60 days of the last DLP (data lock
Points)
• Need and frequency of the report submission to the
authorities are subject to local regulatory
requirement.
• Age of a medicinal product on the market may
influence the process.
• product marketed for several years, need
comprehensive PSUR and frequency of reporting
may be reviewed depending upon local regulation.
 Restarting the Clock
• Approvals beyond the initial approval for the active
substance may be granted for reasons including
– new indication
– Dosage forms
– Routes of administration
– Populations beyond those for which the active
substance was initially authorized.
• Safety profile of new types and extent of population
exposure may influence the requirement for periodic
reporting, necessitating discussion between regulatory
authorities and MAH
• Proposed amendment to the PSUR submission cycle
should be submitted with reasoned request along with
application for marketing authorization.
 Reference Safety Information
• Company Core Safety information(CCSI)
– derived from Company core data sheet (CCDS)
– Contains all relevant safety information
required by the company to be listed for the
drug in all countries where it is marketed
• CCSI will determine whether an ADR is listed or
unlisted, as opposed to labelled or unlabelled.
• Labelledness is country specific whereas listedness
is uniform across all the countries and therefore it
must be determined for the PSUR.
– labelledness is based on SmPC Summary of
Product Characteristic for the purpose of local
expedited post authorization safety reporting.
 Description of the reaction

• Verbatim reporter term as well as standardized

coding term (i.e MedDRA,which was approved after
E2C was finished) should be used.
• FDA replaced its spontaneous reporting system and
its conventional dictionary, the Coding Symbols for a
Thesaurus of Adverse Reaction Terms, with new
adverse events reporting system and the MedDRA
terminology
• MedDRA is important part of the electronic database
system used by European and Japanese authorities.
 Regulatory Requirements
• ICH E2C is followed in all three ICH regions, however the
reporting requirements differ in these region:
– EU,Council Directive/93/39/EEC and Council
Regulation
• Report should be submitted every 6 months for
first 2 years, annually for next three years and
then five yearly after the first renewal
– USFDA-quarterly reports during first 3 years, then
annual reports
– Japan-survey on cohort of a few thousand pts.
Established by a certain number of identified institutions
during 6 years following authorization.
• Adverse reactions which are non-serious, but both
mild in severity & unlabelled, must be reported 6
monthly for 3 years and annually thereafter.
Section number
Content
Section
of PSUR
Executive Summary

1.1 Introduction

1.2 Worldwide Market Authorization

1.3 Update on regulatory authority or market authorization holder
action taken for safety reasons
1.4 Changes in reference safety information
1.5 Patient exposure
1.6 Presentation of individual case histories
1.7 Studies
1.8 Other information
1.9 Overall safety evaluation
1.10 Conclusion
Appendix 1 Company Core Data Sheet
Appendix 2 Marketing Authorization status
Appendix 3 Line listing of Case Report
Appendix 4 Summary tabulations of events
 PSUR content
• Title
– Statement of confidentiality of the data and
conclusions included in the report
• Executive Summary
– Brief overview providing the reader with a
description of the most important information
• Introduction
– Sets the scene and puts the report in context
– Cross referencing it to previous reports
– Describing products/formulation that are included
and excluded
– Pharmacology of the product
– Indications and co-licensing agreements
 PSUR Contents Cont...
• Worldwide Marketing Authorization Status
– A table with dates of market authorization and
renewals, indications, lack of approvals,
withdrawals, date of launch and trade names
• Update on Regulatory Authority or MAH Actions
taken for Safety Reasons:
– Marketing authorization, withdrawal or suspension
– Failure to obtain a marketing authorization renewal
– Restriction on distribution
– Clinical trial suspension'
– Dosage modification/ formulation changes
– Changes in target population or indications
– It should discuss the safety related reasons that
led to the actions described & append the
appropriate documentation.
 PSUR Content Cont...
• Changes in Reference Safety Information
– Change in the CCSI
– The CCDS, which incorporates the CCSI, should be
included as an appendix
– If no CCDS is available, a national SPC can be used.
– If there is a time lag between changes to the CCDS
and local labeling, this should be commented on
when submitting to that local health authority.
• Patient Exposure
– Both market exposure and clinical trials.
– Estimates rely on gross approx. of in-house or
purchased sales data or volume.
– This includes patient exposed, patient-days,
number of prescriptions and tonnage sold.
 PSUR content cont....
Presentation of Individual Case Histories
• Follow up data on previously reported cases
• Literature should be monitored and cases included.
• Duplicate should be avoided.
• If a case is mentioned in the literature, even if obtained also
as a spontaneous or trial case, the citation should be noted
• If medically unconfirmed cases received from consumers
should be submitted as addenda line listing and summary
reports
• Line listing should include each pt. Only once. If a patient has
more than one ADR, the case should be listed under the most
serious adverse drug experience with the others also
mentioned there.
• More than one listing for different dosage forms and indication
is advisable
 PSUR Content cont...
Presentation of Individual Case Histories
• The headings for the listings are:
– MAH reference number
– Country where the case occurred
– Source (trial, literature,spontaneous, regulatory
authority)
– Age and Sex
– Daily dose, dosage form and route of suspected
drug
– Reaction onset date
– Treatment dates
– Description of the reaction (MedDRA code)
– Patient outcome at the case level (resolved)
– Comments
 PSUR Content Cont....
Presentation of Individual Case Histories
• Line listing should include the following causes:
– Spontaneous reports: all serious reactions, non-
serious unlisted reaction
– Studies or compassionate use
– Literature:all serious and non-serious reaction
– Regulatory authority cases: all serious reactions
– If nonserious, listed ADRs are required by some
authorities, they should be reported as an
addendum
• Summary tabulation
– Data in summary tabulation should be non-
cumulative except for ADRs, which are both serious
and unlisted for which cumulative figure should be
provided in the table
 PSUR Content Cont....
• Studies
– Refers to only those company-sponsored
studies and published safety studies, including:
• Epidemiology studies
– Producing findings with potential impact on product
safety information.
– Should be included along with a discussion of any
final or interim results.
• The MAH should not routinely catalog or
describe all the studies.
• Other Information
– May include risk management programmes led by
MAH and/or a benefit-risk analysis report
– Lack of efficacy information should be presented
here
– Late-breaking information after database lock
 PSUR Content Cont....
Overall Safety evaluation

Should highlight new information on serious and non-
serious unlisted ADRs.

The data should be presented by system organ class and
should discuss:
• A change in • Drug Interactions
characteristics of listed • Overdose and its
reaction'
treatment
• Serious unlisted • Drug misuse or abuse
reactions, placing into
perspective the • Pregnancy and lactation
cumulative reports information
• Nonserious unlisted • Experience in special
reactions patient groups
• Increased frequency of • Effects of long-term
listed reaction treatment
• New Safety issues
 PSUR Content Cont....

• Conclusion
– Should indicate safety data which are not in
accordance with previous experience and with
company CCSI
– Any action recommended or initiated
• Appendix:
– Company Core Data Sheet (CCDS)
 Summary Bridging Reports
• Integrates two or more PSURs that is submitted to
regulatory authority to cover a specific time period for
which a single report is required.
• It should not contain new data or repeat the information
already included in the PSURs but should cross
reference those other reports.
• format/outline should be identical to the format of the
usual PSUR but the content should consist of summary
highlights.
• It should not contain line listing but may have summary
tables.
 Addendum Reports
• It is used when it is not possible to synchronize PSURs
for all authorities requiring submissions
• It is an update to the most recently completed and
scheduled PSUR that is produced when regualtor
requires a safety update outside the usual reporting
cycle,and more than a brief amount of time has elapsed
since the DLP of the most recent PSUR.
• It should contain:
– Introduction
– Any changes to the CCSI
– Significant regulatory actions on safety
– Line listing and/or summary tabulations and a
conclusion.
 The PSUR Process
• Comprises of the following steps:
– Intake of ADR information
– Case processing
– Data retrieval
– Data analysis
– Medical review and risk assessment
• After reporting of ADR, the case is entered into a
safety database, a narrative is prepared and a
MedDRA term is assigned to ADRs
 PSUR Process
• Can be illustrated by the standard operating
procedure (SOP) of H.Lundbeck A/S.
• There are five stages to Lundbeck's procedure:
– Data collection
– PSUR writing
– Approval
– Archiving
– distribution
 Conclusion
• PSUR
– Source for the identification of new safety signals
– A means for determining changes in the benefit-risk
profile
– Effective means of risk communication to regulatory
authorities
– Indicator for the need for risk management
– Provide opportunity to review aggregate data
– Gives chance to detect potential problem as pt.
Exposure increases in response to promotional
efforts
– Tool for monitoring the unpromoted use of drug in
subpopulation (children, elderly patient etc.)
Thank you