The aim of Safety reports is describe the safety during the lifecycle of the medicinal product. These reports are necessary during development as well as during the authorization process or renewal. In addition, several of these reports may be required by Health Authorities in case of safety concerns.
This presentation contains a full overview about periodic safety update reports and all the information related with it.
1. What is a Periodic Safety Update Report (PSUR)?
2. Objective of the PSUR
3. Periodicity, EU Reference Dates and Data lock Points
4. Exemption from submitting PSURS
5. EU single assessment of PSUR (PSUSA)
6. Summary of GVP Module VII
7. How to review a PSUR/PBRER
Safety Reports: PSUR/PBRER
1. WHAT IS A PERIODIC SAFETY REPORT (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.
PBRER (Periodic Benefit Risk Evaluation Report) are referred to as PSUR
since implementation in Europe via GVP module VII.
2. OBJECTIVE OF THE PSUR (1)
To present a comprehensive and critical analysis of new or emerging
information on the risks and, where pertinent, new evidence of benefit to
enable an appraisal of overall benefit risk.
To contain an evaluation of new relevant information that became available to
the MAH during the reporting interval, in the context of cumulative
• Examine whether new information is in accord with previous knowledge of
the benefit risk profile
• Summarises relevant new safety information that may impact the benefit
• Summarises any important new efficacy and effectiveness information
• Conduct an integrated Benefit/Risk evaluation (where new important safety
information has emerged)
2. OBJECTIVE OF THE PSUR (2)
This evaluation of risk-benefit assessment should be undertaken in the
context of ongoing pharmacovigilance and risk management:
Module VII: Post-authorization safety studies
Module V: Risk management systems
3. PERIODICITY (1)
PSUR must be prepared at the following intervals:
• Immediately upon request
• Every six months from authorisation until product placed on the market
• Every six months for first two years on the market
• Annually for the next two years
• Thereafter every 3 years
Exception – frequency and dates of submission are laid down as a condition of the MA
or determined otherwise in the list of Union Reference Dates (EURD List).
• By day 70 for intervals up to 12 months
• By day 90 for intervals in excess of 12 months
3. INTERNATIONAL BIRTH DATE AND DATA LOCK POINT (2)
The date of the first marketing approval for the medicinal product in
any country in the world is the International Birth Date (IBD). Data
lock point is the date designated as the cut-off for data to be included,
based on IBD.
The EU Reference Dates List is a comprehensive list of active
substances and combinations of active substances for which PSURs
shall be submitted:
• Legally binding
• Periodicity defined on a risk-based approach
The EU Reference Dates List was put in place in order to facilitate the
harmonisation of Data Lock Points (DLPs) and frequency of
submission of PSURs for medicinal products containing the same
active substance or the same combination of active substances
subject to different marketing authorisations, authorised in more than
one Member State.
EMA has published the list of Union reference dates and frequency of
submission information which will be legally binding when Module VII
becomes effective 2 July 2012.
3. EU REFERENCE DATES LIST (3)
EU reference dates list
3. EU REFERENCE DATES LIST (4)
The EURD list is a living document which will be amended whenever
considered necessary by the PRAC, the CHMP or CMDh in response to
the emergence of relevant new safety information, newly authorised
substances and requests received from MAHs. Substances can be
added or removed as appropriate. The EURD list is updated on a
monthly basis; MAHs should therefore maintain an awareness of the
current status of the list. PSURs shall also be submitted at any time
immediately upon request by the regulatory authorities.
3. EU REFERENCE DATES LIST (EURD List) (5)
3. EU REFERENCE DATES LIST (EURD List)
REGULATORY NETWORK (6)
The Co-ordination Group for Mutual Recognition and
Decentralised Procedures – Human, examine any question
relating to marketing authorisation of a medicinal product in
two or more Member States in accordance with the mutual
recognition procedure or the decentralised procedure.
Executive body of the European
Union responsible for proposing
decisions, upholding the Union's
treaties and day-to-day running of
Helps protect and promote health in Europe by evaluating
medicines for both human and veterinary use.
Heatlh Authorities of each Member State
The Committee for Medicinal Products for Human Use is the
committee at the EMA that is responsible for preparing
opinions on questions concerning medicines for human use.
The committee at the EMA that is responsible for assessing
and monitoring safety issues for human medicines.
National Competent Authorities (NCA)
4. EXEMPTION FROM SUBMITTING PSURS
Generics, well-established use, and traditional herbal medicinal
products are exempted from submitting PSURs except in the
The marketing authorisation provides for the submission of
PSURs as a condition.
PSURs is (are) requested due to concerns relating to PV data or
due to the lack of PSURs relating to an active substance after
the MA has been granted (e.g. when the “reference” medicinal
product is no longer marketed).
For the products where PSURs are no longer required to be
submitted routinely, it is expected that marketing authorisation
holders will continue to:
• Evaluate the safety of their products on a regular basis and
Report any new safety information that impacts on the benefit-
risk profile or the product information.
5. EU SINGLE ASSESSMENT OF PSUR (PSUSA) (1)
PSUSA is a PSUR single assessment of substances contained in
centrally authorised product(s) AND nationally authorised
products. This assessment lead to legally binding outcomes:
maintenance, variation, suspension, revocation of the marketing
Objectives: harmonise and strengthen the safety and benefit-risk
review of medicines across the EU; increase the shared use of
resources between competent authorities; Assessment by the
PRAC with CHMP involvement (for CAP and CAP/NAP) or CMDh
(for NAP) in case of regulatory action.
5. EU SINGLE ASSESSMENT OF PSUR (PSUSA) (3)
The EMA publishes a list of outcomes for NAPs on their website
while outcomes for CAPs are published as part of each medicine’s
European public assessment report (EPAR). Any changes to the
product information as a result of the PSUR assessment are
implemented without subsequent variation for CAPs and through
the appropriate variation at national level for NAPs.
6. SUMMARY OF GVP MODULE VII
Module VII includes guidance on the objectives, format and contents of the
PSUR, as well as recommendations for quality systems for PSURs and training
of staff members on the PSUR process.
PSURs should provide greater emphasis on analysis of case reports; to
scientific evaluation of the benefit-risk profile
summaries of relevant scientific/clinical data including literature searches
available sales/prescription data to calculate patient exposure
The reaction terms used in the PSUR should be in accordance with the
7. HOW TO REVIEW A PSUR/PBRER
Review by an experienced person who knows the drug and who knows
HIGH QUALITY /AUDITS/ INSPECTIONS
• All promises and commitments made to the Health Agencies (HAs), whether in
the PSUR itself or in accompanying emails or communications should be noted.
Responses to HAs.
• Make sure you have in hand the appropriate labels (CCSI, national labeling etc.).
• The reviewer should be aware of any current concerns (safety signals, special
populations, new or removed indications, any actions taken for safety reasons by
the company or another health agency, any label changes for safety reasons
anywhere in the world….)
• Careful review of the SAEs/ADRs:
• In which SOCs have most SAEs/ADRs occurred?
• Any surprises or signals in the listed SAEs/ADRs?
• Any surprises or signals in the unlisted SAEs/ADRs?
• Any surprises or issues in the fatal SAEs/ADRs?
• Are there any findings in specific patient populations as defined by disease, age,
vulnerable groups etc?
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