PART 3

Periodic Safety Updated

Report (PSUR)
GVP Module VII
WHAT IS PSUR?
- Pharmacovigilance documents
- Provide concise, comprehensive, critical risk-benefit evaluation of health product.
- Submitted at defined time points after receiving marketing authorization.

PSUR vs PBRER
- PSUR and PBRER are interchangeable vocabulary.
- PBRER was introduced in ICH guideline E2C(R2) in2012 (Risk → benefit-risk)
- PSUR is used in EU (e.g. GVP module 7)
- PBRER is used in Malaysia.
Component of PSUR
• Introduction:
• Structures and processes
• Operation:
• Appendices:
A) Introduction
• What is PSUR
• Legal requirement of PSUR
• Regulation (EC) No 726/2004
• Directive 2001/83/EC and in the Commission Implementing Regulation (EU) No 520/2012
• Regulation (EC) No 726/2004 and
• Directive 2001/83/EC

• Overview of the medicinal product

- Active substance
- Indications
- Authorization details
- Purpose of the PSUR.
B) Structures and processes
The systems, processes, and organizational structures they have in place to ensure
pharmacovigilance and monitor the safety of their medicinal products.

• Objective of PSUR
• Principles for evaluation
• Principle for preparation of PSUR
• Reference information
• Format and contents of the PSUR
• Quality system of PSUR (MAH Level)
• Training of PSUR process
B) Structures and processes
• Objective of PSUR ✓ Comprehensive & critical
analysis of the risk- benefit
• Principles of Evaluation
✓ Update and accumulate
• Principle for preparation of PSUR risk-benefits information
• Reference information
• Format and contents of the PSUR
• Quality system of PSUR (MAH Level)
• Training of PSUR process
B) Structures and processes
• Objective of PSUR

• Principles of Evaluation
• Principle for preparation of PSUR
• Reference information
• Format and contents of the PSUR
• Quality system of PSUR (MAH Level)
• Training of PSUR process
 Data collection Communication continual evaluation
- latest available safety data - healthcare professionals
Updated PSUR → ensure the
- Acquire data from all relavant - regulatory authorities
ongoing risk-benefit evaluation of
sources (RCT, PV, literature, etc) - patients as appropriate.
the product throughout its lifecycle

PRINCIPLES
Benefit-risk assessment

Risk management compliance

Provide risk-benefit assessment of the
Evaluate the effectiveness of with regulatory requirements product's based on the lates safety
risk management measures and guidelines. data and the product's intended use.
and adjust the measures
when necessary
B) Structures and processes
• Objective of PSUR ✓ Component:
1) core safety
• Principles of Evaluation 2) authorized indication(s)
• Principle for preparation of PSUR ✓ Must be in English
✓ Briefly provide ongoing procedures to
• Reference information update PI (required in EU regional appendix)
Note:
• Format and contents of the PSUR • Proposed PI is required in GVP Module VII
• Quality system of PSUR (MAH Level & Agency • If important safety information is missing in
the PI, MAH should propose a relevant
level) wording within the PSUR.
• Training of PSUR process
FORMAT & CONTENTS OF PSUR
B) Structures and processes
• Objective of PSUR
• Principles of Evaluation
• Principle for preparation of PSUR
• Reference information
• Format and contents of the PSUR MAH: Structures and processes for
data preparation, quality control, review
• Quality system of PSUR (MAH) and submission of PSURs including
follow-up during and after their
• Training of PSUR process assessment.
C) Operation
• Standard submission schedule of PSURs
Frequency of submission
• Transparency
• Renewal of marketing authorisation
 STANDARD PSUR SUBMISSION SCHEDULE
(EMA)
Marketed

1st yr 2nd yr 3rd yr 4th yr 5th-7th yr

6 monthly yearly 3-yearly

A review from 43 countries:

- 42 countries require PSUR submission every 6 month during the first 2 yrs.
- 1 country requires PSUR submission every 4 month during first 2 yrs.
TRANSPARENCY
• List of EU reference date and frequency of submission of PSURs.
• Final assessment conclusions of the adopted assessment reports.
• PRAC recommendations including relevant annexes.
• CMDP positions including relevant annexes and where applicable.
• CHMP opinions including relevant annexes and where applicable.
• European commission decision.
Renewal of Marketing Authorizations
• Normal MA renew every 5 years.
• Conditional MA renew every year.
• No need to submit PSURs, addendum and summary reports with the renewal
application.
D) APPENDICES
•Estimated cumulative subject exposure from clinical
trials.
•Cumulative exposure from marketing experience.
•Numbers of adverse reations by preferred term
from post-authorisation sources.
•The tabular summary of safety signals ongoing or
closed during the reporting interval .
Discussion points:
1. PSUR is necessary for monitoring of the health product safety
information. What products should be included for PSUR?
• New Drug
• NCE, NBE (originator)
• New indication, New combination, New strength, New
Route, New Dosage form, New delivery system

• New generic, New Biologic, Biosimilar

Discussion points:
2. Whether the submission timeline appropriate?
• Every 6 month for the first 2 yrs
• Every 1 year for yr 3-4
• Every 3 year after 4th yr

3. Content to be written in ThGVP

COMPARISON OF PSUR ACROSS COUNTRIES
PSUR component EMA USA MAL THA
Introduction ✓ ✓ ✓ ✓
Structure and process ✓ ✓ ✓ ✓
Objective ✓ ✓ ✓ ✓
Principle for evaluation ✓ ✓
Principle for preparation ✓ ✓ ✓ ✓
Reference information ✓ ✓ ✓
Format ✓ ✓ ✓ ✓
Quality system of PSUR (MAH Level) ✓ ✓
Training of PSUR process (EU context) ✓
Operation ✓ ✓ ✓
Standard submission schedule ✓ ✓ ✓ ✓
Transparency ✓ ✓
Renewal of MA ✓ ✓
Appendiices ✓ ✓ ✓
Q&A
Post-Authorization Safety
Studies (PASS)
GVP Module VIII

1
What is PASS?
‒ Any study relating to an authorized medicinal product.

‒ Aim of PASS:
• Identifying a safety hazard
• Characterizing a safety hazard
• Quantifying a safety hazard
• Confirming the safety profile of the medicinal product
• Measuring effectiveness of risk management measures

‒ PASS is initiated, managed or financed by the MAH;

• voluntary or
• obligation
5
7
When to conduct PASS?
• Voluntarily by marketing authorisation holder (MAH)
• Pursuant to an obligation imposed by an EU competent
authority
⚬ Imposed as condition of marketing authorisation
⚬ Specific obligation under exceptional circumstances
authorization
⚬ Required in PV plan under RMP

7
Number of PASS 1as of 3/5/23
Finalised Ongoing

Category 1
Imposed as condition of
marketing authorisation

Category 2
Specific obligation of
marketing authorisation

Category 3
Required in RMP

11 0 100 200 300 400

Study designs
• Active surveillance: Registry, intensive monitoring scheme,
cohort event monitoring
• Observational studies: Cross-sectional, case only, case-
control, cohort
• Clinical trials
• Drug utilisation studies : real world study

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Report & Publication
• Reporting
⚬ Data relevant to risk-benefit balance of the product (What/When/How)
⚬ ADRs data management
⚬ Progress & interim report (What/When)
⚬ Final study report (Time/Content)

• Publication
⚬ MAH should agree in advance on a publication policy

1
Others
• Data protection
⚬ Ensure the confidentiality of records
• Quality systems
⚬ Ensure that it can be audited, inspected and verified

13
Actions
• Evaluate the impact on the marketing authorisation
• Recommendation by PRAC (or competent authority)
⚬ Variation
⚬ Suspension
⚬ Revocation

16
Discussion point
PASS is one of the component in the GVP
1. Do you agree that there should be a detail guideline
of PASS written?
2. Compare to the table of content in other countries,
which content should be included?

16
 PASS - Post Authorization Safety Study
EMA USA MAL THA SG JAP KOR
A. Introduction
A.1. Terminology ✔ ✔ ✔ ✔ ✔ ✔

B. Structures and processes

B.1. Principles ✔ ✔ ✔ ✔ ✔ ✔
B.2. Study registration ✔ ✔
B.3. Study protocol ✔ ✔ ✔ ✔
B.3.1. Format and content of the study protocol ✔ ✔ ✔ ✔
B.3.2. Substantial amendments to the study protocol ✔ ✔
B.4. Reporting of pharmacovigilance data to competent authorities ✔ ✔ ✔ ✔ ✔
B.4.1. Data relevant to the risk-benefit balance of the product ✔ ✔
B.4.2. Reporting of adverse reactions/adverse events ✔ ✔ ✔ ✔
B.4.3. Study reports ✔ ✔ ✔
B.4.3.1. Progress report and interim report of study results ✔ ✔
B.4.3.2. Final study report ✔ ✔ ✔
B.5. Publication of study results ✔ ✔
B.5.1. Submission of manuscripts accepted for publication ✔
B.6. Data protection ✔ ✔ ✔
B.7. Quality systems, audits and inspections ✔ ✔ ✔
B.8. Impact on the risk management system ✔
 PASS - Post Authorization Safety Study
EMA USA MAL THA SG JAP KOR

C. Operation of the EU network

C.1. Procedure for imposing post-authorisation safety studies ✔

C.1.1. Request for a PASS as part of the initial marketing authorisation application ✔

C.1.2. Request for a PASS during a post-authorisation regulatory procedure ✔

C.1.3. Request for a PASS due to an emerging safety concern ✔

C.1.4. Joint post-authorisation safety studies ✔

C.1.5. Written observations in response to the imposition of an obligation ✔

C.2 Supervision of non-interventional PASS conducted pursuant to an obligation ✔

C.2.1. Roles and responsibilities of the marketing authorisation holder ✔ ✔ ✔

C.2.2. Roles and responsibilities of the PRAC and the national competent authority ✔ ✔

C.2.3. Roles and responsibilities of the Agency ✔

C.3. Changes to the marketing authorisation following results from a non-interventional PASS ✔ ✔

Appendix

App 1.1. Study designs ✔ ✔ ✔ ✔ ✔

App 1.2. Data sources ✔ ✔ ✔

Surveys ✔

Research ✔
 ADB2

Signal Management
WHO-UMC and
GVP MODULE IX

1
2
5
What is signal?
Signal is information
• Arising from one or multiple sources
• Which suggests a new potentially causal association, or a
new aspect of a known association between intervention
and event either adverse or beneficial

“The evidence in a signal is rarely conclusive. It is uncertain and is only an

early preliminary indication, as it may change over time as more data
accumulates, particularly with regard to the strength of the causal
relationship” 5
Sources of signal
MAH
DRA ICSRs
website

Source
Systematic
Review &
of Active
survielance
Literatures Signal

Epi Clinical
trial
demiological
study

5
Signal detection
Primarily based on spontaneous report

Qualitative
- Manual screen
- Medical review of ICSRs
- Review case series

Quantitative
- Simple cross-tabulations for disproportionality
- Data-mining algorithms

6
Signal validation (signal or not)
‒ Quality of reports
‒ Previous knowledge
• SmPC
• RMP
• PSUR
‒ Strength of the evidence
• #cases
• consistency of the evidence e.g. onset, pattern
• Dose response
‒ Clinical relevance and context
• Frequency
• seriousness, severity
• reversibility of the event
• event in vulnerable subjects
6
Prioritizing the signals (which one to be further investigate)

- Whether the potential association is new .

- Strength and consistency of evidence support the association
- Impact on patients (severity, reversibility, potential for prevention
and clinical outcome)
- Consequence of discontinuation/other therapeutics options
- Public health impact

8
Signal assessment (new risk is real?, need any regulatory action?)
taking into account all available evidence, to determine whether there are new risks causally associated with the active
substance or medicinal product or whether known risks have changed. This review may include non-clinical and
clinical data and should be as comprehensive as possible regarding the sources of information.

- Review internal and external sources to obtain further information.

- Document the risk assessment of the signal.
- Assess the significance of a signal.

8
Recommendation for action (MAH perspective)
MAH should
- provide additional data for assessment.
- provide additional info in the PSUR or submit an ad-hoc PSUR.
- update the product information through an application for a
variation
- submit an RMP or to update the RMP
- implement additional risk minimization measures e.g.
- educational materials
- dissemination of a Direct Healthcare Professional
Communication (DHPC)
- Conduct a post-authorization study (PASS)
8
Discussion
1. Do you agree that the “Signal Management” should be described in
GVP.

2. Proposal of the content of “Signal Management”

8
 Signal Management
มี guideline อยู่แล้วแต่เป็ น internal guideline ของอย EMA UMC USA MAL THA SG JAP KOR
A. Introduction
A.1. Terminology ✔ ✔ ✔ ✔ ✔ ✔
A.1.1. General terminology ✔ ✔ ✔ ✔ ✔ ✔
A.1.2. Terminology specific to the EU signal management process with oversight of
✔
the PRAC
B. Structures and processes
B.1. Sources of data and information ✔ ✔ ✔ ✔ ✔ ✔ ✔
B.2. Signal detection ✔ ✔ ✔ ✔ ✔d ✔ ✔
B.3. Evaluation during signal validation and further assessment ✔ ✔ ✔ ✔ ✔ ✔ ✔
B.4. Signal prioritisation ✔ ✔ c ✔ ✔ ✔
B.5. Quality requirements ✔ ✔a ✔ ✔ ✔ ✔
C. Operation of the EU network
C.1. Roles and responsibilities ✔ ✔ ✔ ✔ ✔ ✔ ✔
C.1.1. Responsibilities of the marketing authorisation holder in the EU ✔ ✔ ✔ ✔

C.1.2. Responsibilities within the EU regulatory network ✔ ✔ ✔ ✔ ✔ ✔

C.2. Emerging safety issues ✔ ✔ ✔
 Signal Management
EMA UMC USA MAL THA SG JAP KOR
C. Operation of the EU network
C.3. Monitoring of EudraVigilance data (Thai vigibase) ✔ ✔ ✔ ✔

C.3.1. Principles for access ✔

C.3.2. Periodicity of monitoring ✔ ✔

C.3.3. Analysis of EudraVigilance data (Thai vigibase) ✔ ✔ ✔ ✔

C.4. Notifications and procedural options for signals detected by the MAH based on the continuous monitoring
✔
of EudraVigilance data
C.4.1. Variation of the terms of marketing authorisation ✔ ✔ ✔

C.4.2. Inclusion of the signal in the periodic safety update report (PSUR) ✔

C.4.3. Standalone signal notification ✔

C.5. Signal confirmation by the PRAC rapporteur or (lead) Member State ✔ ✔ ✔ ✔

C.6. Signal analysis, prioritisation and assessment by the PRAC ✔ ✔ ✔ ✔ ✔

C.7. Recommendations on signals from the PRAC (Thai signal panel, อนุกรรมการ ADR = Safety subcommittee)
✔ ✔ ✔ ✔ ✔ ✔

C.8. Record management in the European Pharmacovigilance Issues Tracking Tool (EPITT) ✔

C.9. Transparency ✔

When further expert resources are needed ✔ ✔

Discuss with experts ✔ ✔

Pharmacoepidemiologic studies ✔b ✔ ✔

Registries ✔b ✔

Surveys ✔b

Collaborations ✔