Health Product

GOOD
Vigilance Center,
Food and Drug
Administration,

PHARMACOVIGILANCE Thailand, Ministry of

Public Health

PRACTICE ADB Healthcare

project

December 15 , 2023

Thailand
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GOOD PHARMACOVIGILANCE PRACTICE

THAILAND 2023

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 PREFACE

Pharmacovigilance (PV) is a crucial process that involves detecting, assessing, understanding, and
preventing adverse effects or other potential drug-related issues associated with medications, according
to the World Health Organization (WHO). Its primary objective is to ensure drug safety and optimize the
benefit-risk ratio of a pharmacological product throughout its life cycle.

Ensuring patient safety for medicinal products is of utmost importance, and the responsibility of PV is
shared among various entities such as National regulatory authorities, marketing authorization holders
(MAH), healthcare professionals, and consumers.

To serve as the national database for adverse drug reactions in the country, the Adverse Drug Reaction
Monitoring Center (ADRMC) was established in 1983 under the Food and Drug Administration of Thailand
(Thai FDA), Ministry of Health, Thailand. In 1984, Thailand joined the WHO Program for International Drug
Monitoring as its 26th member. Over time, the ADRMC's scope of responsibilities was expanded to include
other health products besides medicines and other factors that could affect product safety. In 2008, the
ADRMC was renamed the Health Product Vigilance Center (HPVC).

In 2015, guidance on safety reporting of medicinal products was introduced for marketing authorization
holders (MAHs) in Thailand. Later in 2017, a risk management plan was also introduced. The Good
Pharmacovigilance Practice (GVP), which covers the full range of PV processes, was initiated in the
European Union in 2012.

With the support of the Asian Development Bank (ADB), HPVC plans to review and develop the Good
Pharmacovigilance Practice Guidance for Thailand in 2023. In July 2023, several PV guidance sources,
including the European Medicinal Agency (EMA), US FDA, WHO, and other stringent regulatory agencies,
were reviewed and presented to stakeholders. The draft of Thailand GVP guidance 2023 has incorporated
all inputs and is now pending public hearings among all stakeholders in the final stage.

The objective of this guidance document is to outline the optimal approaches for overseeing the safety
and effectiveness of medicinal products, including vaccines, for human use in Thailand. This report serves
as a reference source for implementing best practices in pharmacovigilance and can be utilized to bolster
one's efforts based on their specific product stage and risk level. It's important to note that all individuals
should stay current with and adhere to any applicable regulations within Thailand.

The ultimate goal is to prioritize the safety of patients and the public. Therefore, all responsible persons
involved in pharmacovigilance, both in the public and private sectors, should adhere to high standards of
safety and efficacy. The guidance document comprises 10 chapters, including the quality system of
pharmacovigilance, pharmacovigilance system, inspection, audit, reporting of Adverse Drug Reactions
(ADRs) and Adverse Events Following Immunization (AEFIs), Risk Management Plans (RMPs), safety
communication, Periodic Benefit Risk Evaluation Reports (PBRERs), Post-Authorization Safety Studies
(PASS), and Signal Management.

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Thailand's safety reporting and risk management plan regulations are available. Therefore, our chapters
on both topics (5 and 6) are proposed to include the good pharmacovigilance practice and country
regulations.

Project Lead

Osot NERAPUSEE PhD.

Team collaborator

Wimon SUWANKESAWONG

Puree ANANTACHOTI PhD.

Thawatchai NAKKARATNIYOM

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Preface
Glossary
Chapter 1 Pharmacovigilance System and Quality
Chapter 2 Pharmacovigilance System Master File (PSMF)
Chapter 3 Inspection
Chapter 4 Audit
Chapter 5 Safety Reporting Requirement
Chapter 6 Risk Management Plan (RMP)
Chapter 7 Safety Communication
Chapter 8 Periodic Benefit Risk Evaluation Report (PBRER)
Chapter 9 Post Authorization Safety Study (PASS)
Chapter 10 Signal Management
Reference

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 Table of content
List of tables ..................................................................................................... 12

List of figures .................................................................................................... 12

GLOSSARY ......................................................................................................... 13

Abuse of a medicinal product .................................................................................. 13

Active substance ................................................................................................... 13
Advanced therapy medicinal product (ATMP)............................................................. 13
Adverse event (AE)................................................................................................ 13
Adverse reaction; synonyms: Adverse drug reaction (ADR), Suspected adverse (drug)
reaction, Adverse effect. ........................................................................................ 13
Audit ................................................................................................................... 14
Audit finding(s) ..................................................................................................... 14
Audit plan............................................................................................................. 14
Audit recommendation ........................................................................................... 14
Biological medicinal product .................................................................................... 14
Biosimilar medicinal product ................................................................................... 14
Clinical study ........................................................................................................ 15
Closed signal ........................................................................................................ 15
Company core data sheet (CCDS) ........................................................................... 15
Company core safety information (CCSI) .................................................................. 15
Completed clinical trial ........................................................................................... 16
Consumers ........................................................................................................... 16
Crisis ................................................................................................................... 16
Data lock point...................................................................................................... 16
Development International Birth Date (DIBD) ........................................................... 16
Development Safety Update Report (DSUR).............................................................. 16
Direct healthcare professional communication (DHPC) ................................................ 16
Emerging safety issue ............................................................................................ 16
Excipient .............................................................................................................. 17
Failure to vaccinate. .............................................................................................. 17
Fake drug .......................................................................................................... 17
Generic medicinal product ...................................................................................... 17
Good pharmacovigilance practices (GVP) .................................................................. 17
Healthcare professional .......................................................................................... 17
Herbal drug .......................................................................................................... 18
Herbal products included herbal medicine and herbal health supplements. ..................... 18
Identified risk ....................................................................................................... 18
Immunological medicinal product ............................................................................ 18
Immunization ....................................................................................................... 19
Immunization anxiety-related reaction ..................................................................... 19

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Immunization error-related reaction ........................................................................ 19
Important identified risk and Important potential risk ................................................ 19
Individual case safety report (ICSR); synonym: Adverse (drug) reaction report ............. 19
International birth date (IBD) ................................................................................. 19
Investigational drug ............................................................................................... 19
Investigational medicinal product ............................................................................ 20
Labelling .............................................................................................................. 20
Marketing Authorization Holders ............................................................................. 20
Medication error .................................................................................................... 20
Medicinal products ................................................................................................. 20
Minimum criteria for reporting ................................................................................. 20
Missing information ............................................................................................... 20
Misuse of a medicinal product ................................................................................. 20
Misuse of a medicinal product for illegal purposes ...................................................... 20
Name of the medicinal product ............................................................................... 21
Narcotic drug and psychotropic substances .............................................................. 21
Newly identified signal ........................................................................................... 21
Non-interventional study ........................................................................................ 21
Non-validated signal .............................................................................................. 22
Normal clinical practice .......................................................................................... 22
Occupational exposure to a medicinal product ........................................................... 22
Off-label use ......................................................................................................... 22
Ongoing signal ...................................................................................................... 22
Overdose ............................................................................................................. 22
Package leaflet...................................................................................................... 22
Periodic safety update report (PSUR) ....................................................................... 22
Pharmacovigilance ................................................................................................. 23
Pharmacovigilance system ...................................................................................... 23
Pharmacovigilance system master file (PSMF) ........................................................... 23
Post-authorization safety study (PASS) .................................................................... 23
Potential risk ........................................................................................................ 23
Quality adherence ................................................................................................. 23
Quality control and assurance ................................................................................. 24
Quality of a pharmacovigilance system ..................................................................... 24
Quality planning .................................................................................................... 24
Quality system of a pharmacovigilance system .......................................................... 24
Reference safety information .................................................................................. 24
Refuted signal ....................................................................................................... 24
Registry ............................................................................................................... 24
Risk-benefit balance .............................................................................................. 24
Risk management plan (RMP) ................................................................................. 25
Risk management system....................................................................................... 25
Risk minimization measure; synonym: Risk mitigation activity..................................... 25

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Risks related to the use of medicinal products ........................................................... 25
Safety concern ...................................................................................................... 25
Serious adverse reaction ........................................................................................ 25
Signal .................................................................................................................. 26
Signal analysis ...................................................................................................... 26
Signal assessment ................................................................................................. 26
Signal detection .................................................................................................... 26
Signal management process ................................................................................... 26
Signal prioritization ................................................................................................ 26
Signal validation .................................................................................................... 27
Solicited sources of individual case safety reports ...................................................... 27
Spontaneous report, synonym: Spontaneous notification ............................................ 27
Strength of the medicinal product............................................................................ 27
Substance ............................................................................................................ 27
Summary of product characteristics (SmPC) ............................................................. 28
Target population (treatment); synonym: Treatment target population ........................ 28
Target population (vaccine); synonym: Vaccine target population ................................ 28
Thai traditional drug .............................................................................................. 28
Unexpected adverse reaction .................................................................................. 28
Upper management ............................................................................................... 28
Vaccination ........................................................................................................... 28
Vaccination failure ................................................................................................. 28
Vaccine failure ...................................................................................................... 28
Vaccine pharmacovigilance ..................................................................................... 29
Vaccine product-related reaction ............................................................................. 29
Vaccine quality defect-related reaction ..................................................................... 29
Validated signal..................................................................................................... 29
Well-established medicinal use products .................................................................. 29
ABBREVIATIONS ................................................................................................... 30

Chapter 1 Pharmacovigilance System and Quality ............................................ 31

PV scope in Thailand.............................................................................................. 31
Scope of products ................................................................................................. 31
Training of personnel for PV ................................................................................... 32
Facilities and equipment for PV ............................................................................... 33
Specific procedures in PV system ............................................................................ 33
Record management ............................................................................................. 33
Performance and Effectiveness of the PV Quality System ........................................... 34
Qualified person for pharmacovigilance (QPPV) and Contact person for pharmacovigilance
(CPPV) by MAHs.................................................................................................... 34
The QPPV ‘s role are proposed as follows (but not limited to): .................................. 35
PV tasks subcontracted to a third party. ................................................................... 35

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Chapter 2 Pharmacovigilance System Master File (PSMF) ................................. 36

The PSMF Content: 9 sections................................................................................ 36

1. Person responsible for pharmacovigilance (QPPV) ............................................... 36
2. MAHs ‘s organizational structure ....................................................................... 37
3. Sources of safety data ..................................................................................... 37
4. Computerized systems and databases ............................................................... 37
5. PV processes .................................................................................................. 38
6. PV performance .............................................................................................. 38
7. Quality system of PV ....................................................................................... 39
8. Logbook; Change control, versions, and archiving ............................................... 39
9. Annex to the PSMF .......................................................................................... 40
PSMF presentation ................................................................................................ 41

Chapter 3 Inspection......................................................................................... 42

Inspection types ................................................................................................... 42

1. System and product-related inspections ............................................................. 42
2. Routine and “for-cause” pharmacovigilance inspections ....................................... 42
3. Pre and Post-authorization inspections ............................................................... 43
4. Announced and unannounced inspections ........................................................... 44
5. Remote and on-site inspections ........................................................................ 44
Inspection scope ................................................................................................... 44
1. Scope of routine pharmacovigilance inspections .................................................. 44
2. Scope of for-cause inspections .......................................................................... 45
Inspection process ................................................................................................ 45
1. Preparation step ............................................................................................. 45
2. Conduct of inspection ...................................................................................... 45
Classification of inspection findings.......................................................................... 46
3. Report of inspection ........................................................................................ 46
4. Record management and archiving.................................................................... 46
Role of MAHs ........................................................................................................ 47

Chapter 4 Audits ............................................................................................... 48

Level of audit plan ................................................................................................. 48

1. Strategic level ................................................................................................ 48
2. Tactical level .................................................................................................. 49
3. Operational level ............................................................................................. 49
Actions and follow-up of audits ............................................................................... 49
Competence of auditors ......................................................................................... 50
Quality of audit activities........................................................................................ 50

Chapter 5 Safety Reporting Requirement ........................................................ 51

1 Legal basis for safety reporting .......................................................................... 51

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2 Confidentiality .................................................................................................. 52
3 Definition ......................................................................................................... 52
4 Scope of reporting ............................................................................................. 53
4.1 The scope of event or reaction of concern includes the following domains;....................... 53
4.2 Type of products for monitoring and reporting included products with marketing
authorized license approval and license exemption ; ................................................. 53
5 Reporter........................................................................................................... 54
6 What to report .................................................................................................. 54
6.1 Individual Case Safety Reports (ICSRs) ........................................................... 54
6.2 Emerging safety issue/New safety information ...................................................................... 56
7 Minimum criteria for reporting ............................................................................ 56
8 Data management .............................................................................................. 56

Chapter 6 Risk Management Plan (RMP) ........................................................... 58

Definition ............................................................................................................. 58
Principles of risk management ................................................................................ 59
Responsibilities for risk management ....................................................................... 60
Objectives of RMP ................................................................................................. 61
Content of the RMP ............................................................................................... 61
Part I Product(s) overview .................................................................................... 61
Part II Safety specification ................................................................................... 62
Module SI - Epidemiology....................................................................................... 62
Module SII - Non-clinical part of the safety ............................................................... 62
Module SIII - clinical part of the safety ................................................................... 63
Module SIV - Populations not studied in clinical trials ................................................. 63
Module SV - Post-authorization experience ............................................................... 64
Module SVI - Identified, potential and missing risks .................................................. 64
Module SVII - Summary of the safety concerns ......................................................... 65
Part III: Pharmacovigilance Plan ............................................................................. 66
Routine pharmacovigilance activities ....................................................................... 66
Additional pharmacovigilance activities .................................................................... 66
Part IV: Plans for Post-Authorization Efficacy Studies ................................................. 67
Part V: Risk Minimization Measures ......................................................................... 67
1. Routine risk minimization activities (measures) .................................................. 67
2. Additional risk minimization activities (measures) ............................................... 68
Effectiveness evaluation of risk minimization activities ............................................... 69
Summary of Risk Minimization Measures .................................................................. 69
Part VI: Summary of the RMP ................................................................................. 69
Transparency of RMP ............................................................................................. 69
Requirements of RMP in Thailand ............................................................................ 70
Thailand-specific annex .......................................................................................... 70

Chapter 7 Safety communication..................................................................... 73

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Objectives ............................................................................................................ 73
Principles of safety communication .......................................................................... 73
Target audiences .................................................................................................. 73
Content of safety communication ............................................................................ 74
Types of safety communication ............................................................................... 74
Effectiveness of safety communication ..................................................................... 75

Chapter 8 Periodic Benefit-Risk Evaluation Report (PBRER) .......................... 77

Objectives ............................................................................................................ 77
Scope of the PBRER ............................................................................................... 77
PBRER in Thailand ................................................................................................. 78
PBRER and other documents .................................................................................. 78
Modular approach ................................................................................................. 78
General principles ................................................................................................. 78
1. Single PBRER for an active substance ................................................................ 78
2. PBRER for fixed-dose combination products ........................................................ 79
3. Products manufactured and/or marketed by more than one company .................... 79
4. Reference information ..................................................................................... 79
5. Level of detail within PBRER ............................................................................. 79
6. Efficacy/Effectiveness ...................................................................................... 80
7. Benefit-risk evaluation ..................................................................................... 80
8. Periodicity and PBRER data lock point ................................................................ 80
A. International Birth Date (IBD) and Data Lock Point (DLP) ..................................... 80
B. Managing difference frequencies of PBRER submission ......................................... 80
C. Time interval between data lock point and the submission ................................... 81
9. Format and presentation of PBRER .................................................................... 81
A. Format .......................................................................................................... 81
B. Presentation ................................................................................................... 81
C. ANNEX for PBRER Submission ........................................................................... 83

Chapter 9 Post-Authorization Safety Study (PASS) ........................................... 86

Terminology ........................................................................................................ 86
Structures and processes ...................................................................................... 86
Principles ............................................................................................................. 86
Study registration ................................................................................................ 87
Study protocol ..................................................................................................... 87
Format and content of the study protocol ................................................................ 88
Substantial protocol amendments .......................................................................... 91
Reporting of pharmacovigilance data to NRAs .......................................................... 91
Publication of study results ..................................................................................... 95
Data protection ..................................................................................................... 95

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 Quality systems, audits and inspections ................................................................... 95
Impact on the risk management system .................................................................. 95
Methods for post-authorization safety studies .......................................................... 96
1. Active surveillance ............................................................................................. 96
1.1 Intensive monitoring schemes ................................................................................... 96
1.2. Prescription event monitoring ........................................................................... 96
1.3. Registries ...................................................................................................... 97
2. Observational studies ........................................................................................ 97
2.1. Cross-sectional study ...................................................................................... 97
2.2. Cohort Study ................................................................................................. 97
2.3. Case-control study .......................................................................................... 97
2.4. Case-only designs .......................................................................................... 97
3. Clinical trials ..................................................................................................... 98
3.1. Large simple trials .......................................................................................... 98
4. Drug utilization studies ...................................................................................... 98

Chapter 10 Signal Management ........................................................................ 99

Signal .................................................................................................................. 99
Signal management process: .................................................................................. 99
Structures and processes ....................................................................................... 99
1. Sources of data .............................................................................................. 99
2. Signal detection ............................................................................................ 100
3. Signal validation ........................................................................................... 100
4. Signal prioritization ....................................................................................... 101
Quality requirements ........................................................................................... 102
Role of MAHs ..................................................................................................... 102

REFERENCES ................................................................................................... 103

List of tables
table 1 General requirements for reporting of ICSRs 1 ............................................................................. 55
table 2 RMP component of the product groups in Thailand .................................................................... 72

List of figures
figure 1 Signal management process ....................................................................................................... 101

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GLOSSARY

Abuse of a medicinal product

Persistent or sporadic, intentional excessive use of medicinal products which is accompanied by
harmful physical or psychological effects

Active substance
Any substance or mixture of substances intended to be used in the manufacture of a medicinal product
and that, when used in its production, becomes an active ingredient of that product intended to exert
a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying
physiological functions or to make a medical diagnosis.

Advanced therapy medicinal product (ATMP)

A medicinal product for human use is either a gene therapy medicinal product, a somatic cell therapy
product, or a tissue-engineered product.

Adverse event (AE)

Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal
product and which does not necessarily have a causal relationship with this treatment.
An adverse event can therefore be any unfavorable and unintended sign (e.g. an abnormal
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product,
whether or not considered related to the medicinal product (ICH-E2D).

In the context of a clinical trial: any untoward medical occurrence in a subject to whom a medicinal
product is administered and which does not necessarily have a causal relationship with this treatment
A subject means an individual who participates in a clinical trial, either as recipient of an investigational
medicinal product or as a control.
In the context of pharmacovigilance and outside a clinical trial: any untoward medical occurrence in a
patient to whom a medicinal product is administered and which does not necessarily have a causal
relationship with this treatment (ICH-E2D).
An adverse event can therefore be any unfavorable and unintended sign (an abnormal laboratory
finding), symptom, or disease temporally associated with the use of a medicinal product, whether
or not considered related to this medicinal product (ICH-E2D).

Adverse reaction; synonyms: Adverse drug reaction (ADR), Suspected adverse (drug) reaction,
Adverse effect.
A response to a medicinal product which is noxious and unintended. Response in this context means
that a causal relationship between a medicinal product and an adverse event is at least a reasonable
possibility (ICH-E2A).
An adverse reaction, in contrast to an adverse event, is characterized by the fact that a causal
relationship between a medicinal product and an occurrence is suspected. For regulatory reporting
purposes, if an event is spontaneously reported, even if the relationship is unknown or unstated by the
by healthcare professional or consumer as primary source, it meets the definition of an adverse reaction
(ICH-E2D). Therefore, all spontaneous reports notified by healthcare professionals or consumers are

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considered suspected adverse reactions, since they convey the suspicions of the primary sources,
unless the primary source specifically state that they believe the event to be unrelated or that a causal
relationship can be excluded.
Adverse reactions may arise from use of the product within or outside the terms of the marketing
authorization or from occupational exposure. Use outside the marketing authorization includes off-
label use, overdose, misuse, abuse and medication errors.
In the context of clinical trials, an adverse reaction is defined as all untoward and unintended
responses to an investigational medicinal product related to any dose administered.

Audit
A systematic, disciplined, independent, and documented process for obtaining audit evidence and
evaluating the evidence objectively to determine the extent to which the audit criteria are fulfilled
(ISO 19011)
Benchmarking, reviews of qualifications, risk assessment questionnaires, surveys, or other activities
in which evidence of fulfilment of pharmacovigilance requirements is not independently obtained
and evaluated, would not be regarded as an audit.

Audit finding(s)
Results of the evaluation of the collected audit evidence against audit criteria (ISO19011).
Audit evidence is necessary to support the auditor’s results of the evaluation, i.e. the auditor’s
opinion and report. It is cumulative in nature and is primarily obtained from audit procedures
performed during the course of the audit.

Audit plan
Description of activities and arrangement for an individual audit (ISO19011).

Audit program
Set of one or more audits planned for a specific timeframe and directed towards a specific purpose
(ISO 19011).

Audit recommendation
Describes the course of action management might consider to rectify conditions that have gone awry
and to mitigate weaknesses in systems of management control.
Audit recommendations should be positive and as specific as possible. They should also identify who
is to act on them

Biological medicinal product

A medicinal product, the active substance of which is a biological substance.
A biological substance is a substance that is produced by or extracted from a biological source and
that needs for its characterization and the determination of its quality a combination of physio-
chemical-biological testing, together with the production process and its control.

Biosimilar medicinal product

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A biological medicinal product that contains a version of the active substance of an already
authorized original biological medicinal product (reference medicinal) product in the country and
which has shown similarity to the reference product in terms of quality characteristics, biological
activity, safety, and efficacy based on a comprehensive comparability exercise.

Corrective Action and Preventive Action (CAPA)

CAPA system is one of the elements of a good Quality Management System. It is a useful tool to
implement corrective actions and preventive actions resulting from the investigation of complaints,
product rejections, non-conformances, recalls, deviations, audits, regulatory inspections and findings,
and trends from process performance and product quality monitoring. A structured approach to the
investigation process should be used with the objective of determining the root cause. The level of
effort, formality, and documentation of the investigation should be commensurate with the level of
risk. CAPA methodology should result in product and process improvements and enhanced product and
process understanding.

Clinical study
Any investigation in relation to humans intended: (a) to discover or verify the clinical,
pharmacological, or other pharmacodynamic effects of one or more medicinal products; (b) to
identify any adverse reactions to one or more medicinal products; or (c) to study the absorption,
distribution, metabolism, and excretion of one or more medicinal products; with the objective of
ascertaining the safety and/or efficacy of those medicinal products.

Closed signal
In periodic benefit-risk evaluation reports, a signal for which an evaluation was completed during the
reporting interval (ICH-E2C).
A safety signal can be closed either because it is refuted or because it is determined to be a potential
or identified risk following evaluation (ICH-E2C).
This definition is also applicable to periodic safety update reports.

Company core data sheet (CCDS)

For medicinal products, a document prepared by the marketing authorization holder containing, in
addition to safety information, material related to indications, dosing, pharmacology and other
information concerning the product (ICH-E2C).

Company core safety information (CCSI)

For medicinal products, all relevant safety information contained in the company core data sheet
prepared by the marketing authorization holder and which the marketing authorization holder
requires to be listed in all countries where the company markets the product, except when the local
regulatory authority specifically requires a modification (ICH-E2C).
It is the reference information by which listed and unlisted are determined for the purposes of
periodic reporting for marketed products, but not by which expected and unexpected are
determined for expedited reporting (ICH-E2C).

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Completed clinical trial
Study for which a final clinical study report is available (ICH-E2F).

Compliance:
Conformity and adherence to policies, plans, procedures, laws, regulations, contracts, or other
requirements

Consumers
For the purpose of reporting cases of suspected adverse reactions, a person who is not a healthcare
professional such as a patient, lawyer, friend or relative of a patient or carer (ICH-E2D).

Crisis
a situation where, after assessment of the associated risks, urgent and coordinated action within
the regulatory agency is required to manage and control the situation.
Data lock point
For a periodic safety update report (PSUR), the date is designated as the cut-off date for data to be
included in a PSUR.
For a periodic benefit-risk evaluation report (PBRER), the date designated as the cut-off date for
data to be included in a PBRER is based on the international birth date (ICH-E2C).
For a development safety update report (DSUR), the date designated as the cut-off date for data to
be included in a DSUR is based on the development international birth date (ICH-E2F).
Date includes day and month (ICH-E2F).

Development International Birth Date (DIBD)

Date of first approval (or authorization) for conducting an interventional clinical trial in any country
(ICH-E2F).

Development Safety Update Report (DSUR)

Format and content for periodic reporting on drugs under development (ICH-E2F).

Direct healthcare professional communication (DHPC)

A communication intervention by which important information is delivered directly to individual
healthcare professionals by a marketing authorization holder or by a competent authority, to inform
them of the need to take certain actions or adapt their practices in relation to a medicinal product.
DHPCs are not replied to inquiries from healthcare professionals.

Emerging safety issue

A safety issue considered by a marketing authorization holder to require urgent attention by the
competent authority because of the potential major impact on the risk-benefit balance of the
medicinal product and/or on patients’ or public health and the potential need for prompt regulatory
action and communication to patients and healthcare professionals.
Examples include:
• major safety issues identified in the context of ongoing or newly completed studies, e.g. an
unexpectedly increased rate of fatal or life-threatening adverse events;
• major safety issues/signal identified through the spontaneous reporting system or
publications in the scientific literature, which may lead to considering a contraindication, a
restriction of use of a medicinal product or its withdrawal from the market;

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• major safety-related regulatory actions outside the country, e.g. a restriction of use of a
medicinal product or its suspension.

Excipient
Any constituent of a medicinal product other than the active substance and the packaging material
. Excipients include coloring matters, preservatives, adjuvants, stabilizers, thickeners, emulsifiers,
flavoring, and aromatic substances.

Failure to vaccinate.
An indicated vaccine was not administered appropriately for any reason (CIOMS-WHO7). For
interpreting what is appropriate, consider the explanatory note for Immunization error-
related reaction.

Fake drug
(1) drugs or substances which are wholly or partly an imitation of genuine drugs;
(2) drugs which show the name of another drug, or an expiry date which is false;
(3) drugs which show a name or mark of producer, or the location of the produce the drug, which is
false;
(4) drugs which falsely show that they are in accordance with a formula which has been registered;
(5) drugs produced with active substances which quantity or strength lower than the minimum or
higher than the maximum standards prescribed in the registered formula under section 79 of the Drugs
Act by more than twenty percent. This definition does not include unintentional quality defects and is
without prejudice to infringements of intellectual property rights
Definitions
Substandard also called "out of specification", these are authorized medical products that fail to meet
either their quality standards or specifications, or both.
Unregistered/unlicensed medical products that have not undergone evaluation and/or approval by the
National or Regional Regulatory Authority for the market in which they are marketed/distributed or
used, subject to permitted conditions under national or regional regulation and legislation.
Falsified medical products that deliberately/fraudulently misrepresent their identity, composition or
source.

Generic medicinal product

A medicinal product which has the same qualitative and quantitative composition in active
substances and the same pharmaceutical form as the reference medicinal product, and whose
bioequivalence with the reference medicinal product has been demonstrated by appropriate
bioavailability studies.

Good pharmacovigilance practices (GVP)

A set of measures drawn up to facilitate the performance of the safety monitoring of medicines.

Healthcare professional
For the purposes of reporting suspected adverse reactions, healthcare professionals are defined as
medically qualified persons, such as physicians, dentists, pharmacists, nurses, and coroners, or as
otherwise specified by local regulations (ICH-E2D).

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Herbal drug
a drug derived from a plant, animal or mineral which has not yet been compounded, dispensed or
Herbal product means

Herbal products included herbal medicine and herbal health supplements.

Herbal drug means a drug derived from a plant, animal or mineral which has not yet been compounded,
dispensed or denatured.

(1) herbal drugs and shall also include Thai traditional drugs, developed herbal drugs, traditional
drugs for use in humans under the law on drugs or drugs that are derived from the knowledge of
alternative medicine as prescribed and notified by the Minister, upon the recommendation of the
Committee, for the treatment, cure and relief of human illnesses or the prevention of diseases;
(2) products made from herbs or products of which active ingredients are herbs or are derived from
herbs that are ready for use in humans to improve their health or the function of their body,
strengthen the structure or the function of human body or reduce the risk factors of disease;
(3) substances intended for use as ingredients in the production of herbal products;
(4) other substances prescribed and notified by the Minister upon the recommendation of the
Committee as herbal products.
Herbal products for human use include
• Herbal medicines;
• Herbal health supplements, including health supplements and cosmeceutical products

Identified risk
An untoward occurrence for which there is adequate evidence of an association with the medicinal
product of interest (ICH-E2F).
Examples include:
• an adverse reaction adequately demonstrated in non-clinical studies and confirmed by clinical
data;
• an adverse reaction observed in well-designed clinical trials or epidemiological studies for
which the magnitude of the difference, compared with the comparator group on a parameter
of interest suggests a causal relationship;
• an adverse reaction suggested by a number of well-documented spontaneous reports where
causality is strongly supported by temporal relationship and biological plausibility, such as
anaphylactic reactions or application site reactions (ICH-E2F)
• Adverse reactions included in section 4.8 of the summary of product characteristics (SmPC) are
also considered identified risks, unless they are class-related reactions which are mentioned in
the SmPC but which are not specifically described as occurring with this product (these would
normally be considered as a potential risk)).

Immunological medicinal product

Any medicinal product consisting of vaccines, toxins, serums, or allergen products:
Vaccines, toxins, and serums shall cover in particular agents used to produce active immunity (such as
cholera vaccine, Bacillus Calmette-Guérin (BCG), polio vaccine, and smallpox vaccine), agents used to
diagnose the state of immunity (including in particular tuberculin and tuberculin, purified protein
derivative (PPD), toxins for the Schick and Dick Tests, brucellin) and agents used to produce passive

18
immunity (such as diphtheria antitoxin, anti-smallpox globulin, antilymphocytic globulin).
Allergen products shall mean any medicinal product which is intended to identify or induce a specific
acquired alteration in the immunological response to an allergizing agent.

Immunization
The process of making a person immune.
Immunization anxiety-related reaction
An adverse event following Immunization arising from anxiety about the Immunization (CIOMS- WHO).
Immunization error-related reaction
An adverse event following Immunization that is caused by inappropriate vaccine handling,
prescribing or administration and thus by its nature is preventable (CIOMS-WHO).

Important identified risk and Important potential risk

An identified risk or potential risk that could have an impact on the risk-benefit balance of the
product or have implications for public health (ICH-E2F).
What constitutes an important risk will depend upon several factors, including the impact on the
individual, the seriousness of the risk and the impact on public health. Normally, any risk that is likely
to be included in the contraindications or warnings and precautions section of the product
information should be considered important (ICH-E2C).

Individual case safety report (ICSR); synonym: Adverse (drug) reaction report
Format and content for the reporting of one or several suspected adverse reactions to a medicinal
product that occur in a single patient at a specific point of time.

International birth date (IBD)

The date of the first marketing authorization for any product containing the active substance
granted to any company in any country in the world (ICH-E2C).
If a marketing authorization holder has no information on the actual IBD for a product, it should first
refer to listings of birth dates that some regions develop and make publicly available. If the product
is not included in any listing, it should propose to the regulatory authority a birth date that is based
on the earliest known marketing authorization of the substance and then obtain the regulatory
authority’s agreement (ICH-E2C).
Internal Control
Internal control is an integral process that is effected by an entity’s management and personnel and is
designed to address risk and provide reasonable assurance that in pursuit of the entity’s mission, the
following general objectives are being achieved: executing orderly, ethical, economical, efficient and
effective operations, fulfilling accountability obligations, complying with applicable laws and
regulations and safeguarding resources against loss, misuse and damage.

Investigational drug
Experimental product under study or development. This term is more specific than investigational
medicinal products, including comparators and placebos (ICH-E2F).

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Investigational medicinal product
An investigational medicinal product is a pharmaceutical form of an active substance or placebo
being tested or used as a reference in a clinical trial, including products already with a marketing
authorization but used or assembled (formulated or packaged) in a way different from the authorized
form, or when used for an unauthorized indication, or when used to gain further information about
the authorized form. A medicinal product which is being tested or used as a reference, including as a
placebo, in a clinical trial.

Labelling
Information on the immediate or outer packaging.

Marketing Authorization Holders

An authorized entity to manufacture or import medicinal products into the Kingdom of Thailand

Medication error
An unintended failure in the drug treatment process that leads to, or has the potential to lead to,
harm to the patient.

Medicinal products
Any substance or combination of substances
• presented as having properties for treating or preventing disease in human beings; or
• which may be used in or administered to human beings either with a view to restoring,
correcting or modifying physiological functions by exerting a pharmacological, immunological
or metabolic action, or to making a medical diagnosis

Minimum criteria for reporting

For the purpose of reporting cases of suspected adverse reactions, the minimum data elements for
a case are: an identifiable reporter, an identifiable patient, an adverse reaction and a suspect
medicinal product (ICH-E2D).
In the case of expedited reporting, the individual case safety report shall include at least an
identifiable reporter, an identifiable patient, one suspected adverse reaction and the medicinal
product(s) concerned.

Missing information
Gaps in knowledge about a medicinal product, related to safety or use in particular patient populations,
which could be clinically significant.
It is noted that there is an ICH definition for important missing information, which is: critical gaps in
knowledge for specific safety issues or populations that use the marketed product (ICH-E2C).

Misuse of a medicinal product

Situations where a medicinal product is intentionally and inappropriately used not in accordance
with the terms of the marketing authorization.

Misuse of a medicinal product for illegal purposes

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Misuse for illegal purposes is misuse with the additional connotation of an intention of misusing the
medicinal product to cause an effect in another person. This includes, amongst others: the sale, to
other people, of medicines for recreational purposes and use of a medicinal product to facilitate
assault.
Name of the medicinal product
The name which may be either an invented name not liable to confusion with the common name,
or a common or scientific name accompanied by a trade mark or the name of the marketing
authorization holder.
The common name is the international non-proprietary name (INN) recommended by the World
Health Organization, or, if one does not exist, the usual common name.
The complete name of the medicinal product is the name of the medicinal product followed by the
strength and pharmaceutical form.
Narcotic drug and psychotropic substances

Narcotic drug means any chemical, plant, or substance which upon being consumed has effected both
physical and mind in a significant manner, such as the need to increase consumption dosage
sequentially, withdrawal symptoms when deprived of narcotic drugs, constant severe physical and
mental carving for consumption, and deterioration of general health and shall include chemicals which
are use for the production of narcotic drugs but excluding certain formulae of household medicines
which contain narcotic drugs ingredient under law on drugs.
Psychotropic substance means psychotropic substance which is natural material or is derived from
natural material or any psychotropic substance which is a synthetic substance.

Newly identified signal

In periodic benefit-risk evaluation reports, a signal first identified during the reporting interval,
prompting further actions or evaluation (ICH-E2C).
This definition could also apply to a previously closed signal for which new information becomes
available in the reporting interval prompting further action or evaluation (ICH-E2C).
This definition is also applicable to periodic safety update reports.

Non-interventional study
A clinical study other than a clinical trial. A study where the medicinal product(s) is (are) prescribed
in the usual manner in accordance with the terms of the marketing authorization. The assignment
of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but
falls within current practice and the prescription of the medicine is clearly separated from the
decision to include the patient in the study. No additional diagnostic or monitoring procedures shall
be applied to the patients and epidemiological methods shall be used for the analysis of collected
data.
Thus, a trial is non-interventional if the following requirements are cumulatively fulfilled:
• the medicinal product is prescribed in the usual manner in accordance with the terms of the
marketing authorization.
• the assignment of the patient to a particular therapeutic strategy is not decided in advance by
a trial protocol but falls within current practice and the prescription of the medicine is clearly
separated from the decision to include the patient in the study; and
• no additional diagnostic or monitoring procedures are applied to the patients and
epidemiological methods are used for the analysis of collected data.

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 Non-interventional studies are defined by the methodological approach used and not by the
scientific objectives. Non-interventional studies include database research or review of records
where all the events of interest have already happened (this may include case-control, cross-
sectional, cohort and other study designs making secondary use of data). Non-interventional
studies also include those involving primary data collection (e.g. prospective observational
studies and registries in which the data collected derive from routine clinical care), provided that
the conditions set out above are met. In these studies, interviews, questionnaires, and blood
samples may be performed as normal clinical practice.

Non-validated signal
A signal for which the signal validation process has led to the conclusion that the available
documentation at that point in time does not contain sufficient evidence demonstrating the
existence of a new potentially causal association, or a new aspect of a known association, and that
therefore further analysis of the signal is not warranted .

Normal clinical practice

The treatment regime is typically followed to treat, prevent, or diagnose a disease or a disorder.

Occupational exposure to a medicinal product

For the purpose of reporting cases of suspected adverse reactions, an exposure to a medicinal
product as a result of one’s professional or non-professional occupation.
It does not include the exposure to one of the ingredients during the manufacturing process before
the release as finished product.

Off-label use
Situations where a medicinal product is intentionally used for a medical purpose not in accordance
with the terms of the marketing authorization.
Examples include the intentional use of a product in situations other than the ones described in the
authorized product information, such as a different indication in terms of medical condition, a
different group of patients (e.g. a different age group), a different route or method of administration
or a different posology. The reference terms for off-label use are the terms of marketing
authorization in the country where the product is used.

Ongoing signal
In periodic benefit-risk evaluation reports, a signal remains under evaluation at the data lock point (ICH-
E2C). This definition is also applicable to periodic safety update reports.

Overdose
Administration of a quantity of a medicinal product given per administration or cumulatively which
is above the maximum recommended dose according to the authorized product information. When
applying this definition, clinical judgment should always be applied.

Package leaflet
A leaflet containing information for the user which accompanies the medicinal product.

Periodic safety update report (PSUR)

Format and content for evaluating the risk-benefit balance of a medicinal product for submission by
the marketing authorization holder at defined time points during the post-authorization phase.

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Pharmacovigilance
Science and activities relating to the detection, assessment, understanding and prevention of adverse
effects or any other medicine-related problem (WHO).
In line with this general definition, the underlying objectives of pharmacovigilance:
• preventing harm from adverse reactions in humans arising from the use of authorized medicinal
products within or outside the terms of marketing authorization or from occupational exposure;
and
• promoting the safe and effective use of medicinal products, in particular through providing
timely information about the safety of medicinal products to patients, healthcare
professionals, and the public.
Pharmacovigilance is therefore an activity contributing to the protection of patients’ and public health.

Pharmacovigilance system
A system used by the marketing authorization holder and national regulatory authority to fulfil the
tasks and responsibilities and designed to monitor the safety of authorized medicinal products and
detect any change to their risk-benefit balance.
In general, a pharmacovigilance system is a system used by an organization to fulfil its legal tasks and
responsibilities in relation to pharmacovigilance and designed to monitor the safety of authorized
medicinal products and detect any change to their risk-benefit balance.
Pharmacovigilance system master file (PSMF)
A detailed description of the pharmacovigilance system used by the marketing authorization holder
with respect to one or more authorized medicinal products.

Post-authorization safety study (PASS)

Any study relating to an authorized medicinal product conducted with the aim of identifying,
characterizing, or quantifying a safety hazard, confirming the safety profile of the medicinal product,
or of measuring the effectiveness of risk management measures. A post-authorization safety study
may be an interventional clinical trial or may follow an observational, non-interventional study
design.

Potential risk
An untoward occurrence for which there is some basis for suspicion of an association with
the medicinal product of interest but where this association has not been confirmed (ICH-
E2F).
Examples include:
• non-clinical toxicological findings that have not been observed or resolved in clinical studies;
• adverse events observed in clinical trials or epidemiological studies for which the magnitude
of the difference, compared with the comparator group (placebo or active substance, or
unexposed group), on the parameter of interest raises suspicion of, but is not large enough
to suggest, a causal relationship;
• a signal arising from a spontaneous adverse reaction reporting system.
• an event known to be associated with other active substances within the same class or which
could be expected to occur based on the properties of the medicinal product (ICH-E2F).

Quality adherence
Carrying out tasks and responsibilities in accordance with quality requirements.

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Quality control and assurance
Monitoring and evaluating how effectively the structures and processes have been established and how
effectively the processes are being carried out.

Quality of a pharmacovigilance system

All characteristics of the pharmacovigilance system which are considered to produce, according to
estimated likelihoods, outcomes relevant to the objectives of pharmacovigilance.

Quality planning
Establishing structures and planning integrated and consistent processes.

Quality system of a pharmacovigilance system

The organizational structure, responsibilities, procedures, processes, and resources of the
pharmacovigilance system as well as appropriate resource management, compliance management and
record management.

Reference safety information

In periodic benefit-risk evaluation reports for medicinal products, all relevant safety information
contained in the reference product information (e.g. the company core data sheet) prepared by the
marketing authorization holder and which the marketing authorization holder requires to be listed
in all countries where it markets the product, except when the local regulatory authority specifically
requires a modification (ICH-E2C).
It is a subset of information contained within the marketing authorization holder’s reference product
information for the periodic benefit-risk evaluation report. Where the reference product
information is the company core data sheet, the reference safety information is the company core
safety information (ICH-E2C).
In the context of a clinical trial, if the investigator ‘s brochure is not a summary of product
characteristics, it shall contain a clearly identifiable section called the ‘Reference Safety Information’
(RSI). … the RSI shall contain product information on the investigational medicinal product and on
how to determine what adverse reactions are to be considered as expected adverse reactions, and
on the frequency and nature of those adverse reactions.

Refuted signal
A validated signal which, following further assessment has been determined to be “false”, i.e. a
causal association cannot be established at that point in time. It is noted that for the purpose of the
periodic benefit-risk evaluation report (PBRER) ICH describes refuted signals as signals that,
following evaluation, have been refuted as “false” signals based on medical judgment and a
scientific evaluation of the currently available information (ICH-E2C).

Registry
An organized system that uses observational methods to collect uniform data on specified outcomes
in a population defined by a particular disease, condition, or exposure.

Risk-benefit balance
An evaluation of the positive therapeutic effects of the medicinal product in relation to the risks, i.e.
any risk relating to the quality, safety or efficacy of the medicinal product as regards patients’ health

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or public health.

Risk management plan (RMP)

A detailed description of the risk management system. The risk management plan established by the
marketing authorization holder shall contain the following elements:
(a) an identification or characterization of the safety profile of the medicinal product(s) concerned;
(b) an indication of how to characterize further the safety profile of the medicinal product(s)
concerned; (c) a documentation of measures to prevent or minimize the risks associated with the
medicinal product, including an assessment of the effectiveness of those interventions; (d) a
documentation of post-authorization obligations that have been imposed as a condition of the
marketing authorization
Risk management system
A set of pharmacovigilance activities and interventions designed to identify, characterize, prevent or
minimize risks relating to a medicinal product, including the assessment of the effectiveness of those
activities and interventions.

Risk minimization measure; synonym: Risk mitigation activity

Interventions intended to prevent or reduce the occurrence of adverse reactions associated with the
exposure to a medicine, or to reduce their severity or impact on the patient should adverse reactions
occur.
These activities may consist of routine risk minimization measures (the summary of product
characteristics, the package leaflet, the labelling, the pack size, the legal status of the product, and its
formulation) or additional risk minimization measures (educational programs, controlled access
programs, other additional risk minimization measures).

Risks related to the use of medicinal products

Any risk relating to the quality, safety, or efficacy of the medicinal product as regards patients’
health or public health and any risk of undesirable effects on the environment.

Safety concern
An important identified risk, important potential risk or missing information. It is noted that the ICH
definition of safety concern is: an important identified risk, important potential risk or important
missing information, i.e. includes the qualifier “important” in relation to missing information (ICH-
E2C). The ICH-E2E Guideline uses the terms safety issue and safety concern interchangeably with
the same definition for safety concern as defined in the ICH-E2C Guideline.

Serious adverse reaction

An adverse reaction which results in death, is life-threatening, requires in-patient hospitalization or
prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or
is a congenital anomaly/birth defect.
Life-threatening in this context refers to a reaction in which the patient was at risk of death at the
time of the reaction; it does not refer to a reaction that hypothetically might have caused death if
more severe (ICH-E2D).
Medical and scientific judgement should be exercised in deciding whether other situations should
be considered serious, such as important medical events that might not be immediately life-
threatening or result in death or hospitalization but might jeopardy the patient or might require
intervention to prevent one of the other outcomes listed in the definition above. Examples of such
events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood
dyscrasias or convulsions that do not result in hospitalization or development of dependency or

25
abuse (ICH-E2D).
Any suspected transmission via a medicinal product of an infectious agent is also considered a
serious adverse reaction.

Signal
Information arising from one or multiple sources, including observations and experiments, which
suggests a new potentially causal association or a new aspect of a known association between an
intervention and an event or set of related events, either adverse or beneficial, that is judged to be
of sufficient likelihood to justify verificatory action.
New aspects of a known association may include changes in the frequency, distribution (e.g. gender,
age and country), duration, severity or outcome of the adverse reaction.
For the purpose of monitoring data in the regulatory database, only signals related to an adverse
reaction shall be considered.
For the purpose of Section 16.2 of the periodic benefit-risk evaluation report, signals relate to adverse
effects (ICH-E2C).
Signal analysis

For the signal management process, the Pharmacovigilance Risk Assessment determines whether a
confirmed signal requires further assessment, and if required, to what timeframe and in which
procedural framework, based on an initial analysis of the potential impact of the signal on patients’
or public health and the risk-benefit balance of the concerned medicinal product(s).

Signal assessment
The process of further evaluating a validated signal 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 process may include non-clinical and clinical data and should be as comprehensive as possible
regarding the sources of information.

Signal detection
The process of looking for and/or identifying signals using data from any source (CIOMS VIII).

Signal management process

A set of activities performed to determine whether, based on an examination of individual case
safety reports, aggregated data from active surveillance systems or studies, scientific literature
information or other data sources, there are new risks associated with an active substance or a
medicinal product or whether known risks have changed, as well as any related recommendations,
decisions, communications, and tracking.
The signal management process shall include the following activities: signal detection, signal
validation, signal confirmation, signal analysis and prioritization, signal assessment and
recommendation for action.
Signal prioritization

26
The process, continuously performed throughout signal management, which aims to identify those
signals suggesting risks with a potential important patients’ or public health impact or which may
significantly affect the risk-benefit balance of the medicinal product and thus require urgent
attention and management without delay.

Signal validation
Process of evaluating the data supporting the detected signal in order to verify that the available
documentation contains sufficient evidence demonstrating the existence of a new potentially causal
association, or a new aspect of a known association, and therefore justifies further analysis of the
signal.
This evaluation should take into account the strength of the evidence, the clinical relevance and the
previous awareness of the association.

Solicited sources of individual case safety reports

Organized data collection systems, which include clinical trials, registries, post-authorization
named- patients use programs, other patient support and disease management programs,
surveys of patients or healthcare providers or information gathering on efficacy or patient
compliance. For the purpose of safety reporting, solicited reports should not be considered
spontaneous but classified as individual case safety reports from studies and therefore should
have an appropriate causality assessment by a healthcare professional or the marketing
authorization holder (ICH-E2D).

Spontaneous report, synonym: Spontaneous notification

An unsolicited communication by a healthcare professional or consumer to a company, regulatory
authority or other organization (e.g. the World Health Organization, a regional center, a poison
control center) that describes one or more adverse reactions in a patient who was given one or more
medicinal products and that does not derive from a study or any organized data collection scheme
(ICH-E2D).
In this context, an adverse reaction refers to a suspected adverse reaction.
Stimulated reporting can occur in certain situations, such as after a direct healthcare professional
communication (DHPC), a publication in the press or questioning of healthcare professionals by
company representatives, and adverse reaction reports arising from these situations are
considered spontaneous reports (ICH- E2D), provided the report meets the definition above.
Reporting can also be stimulated by invitation from patients’ or consumers’ organizations to their
members, or a class lawsuit. Reporting made in the context of early post- marketing phase
vigilance (EPPV), e.g. in Japan, is also considered stimulated reporting.

Strength of the medicinal product

The content of the active substances expressed quantitatively per dosage unit, per unit of volume or
weight according to the dosage form.

Substance
Any matter irrespective of origin which may be human (e.g. human blood and human blood
products), animal (e.g. micro-organisms, whole animals, parts of organs, animal secretions, toxins,
extracts, blood products), vegetable (e.g. micro-organisms, plants, part of plants, vegetable
secretions, extracts), chemical (e.g. elements, naturally occurring chemical materials and chemical
products obtained by chemical change or synthesis).

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Summary of product characteristics (SmPC)
Part of the marketing authorization of a medicinal product setting out the agreed position of the
product as distilled during the course of the assessment process. It is the basis of information for
healthcare professionals on how to use the product safely and effectively. The package leaflet is
drawn in accordance with the summary of product characteristics.

Target population (treatment); synonym: Treatment target population

The patients who might be treated with the medicinal product in accordance with the indication(s) and
contraindications in the authorized product information.
Target population (vaccine); synonym: Vaccine target population
Persons who might be vaccinated in accordance with the indication(s) and contraindications in the
authorized product information and official recommendations for vaccinations.

Thai traditional drug

a drug derived directly from herbs or from the mixing, compounding, or processing of herbs, which are
intended for use, based on the Thai Traditional medicine knowledge or the drugs prescribed and
notified by the Minister, as Thai traditional drugs.
Unexpected adverse reaction
An adverse reaction, the nature, severity, or outcome of which is not consistent with the summary of
product characteristics. In the context of a clinical trial, an unexpected serious adverse reaction means
a serious adverse reaction, the nature, severity or outcome of which is not consistent with the
reference safety information (e.g. the investigator’s brochure for an unauthorized investigational
product or the summary of product characteristics for an authorized product)

Upper management
Group of persons in charge of the highest executive management of an organization. They are the head
of the organization with ultimate responsibility for ensuring that the organization complies with
relevant legislation.

Vaccination
The administration of a vaccine with the aim to produce immune response.

Vaccination failure
Vaccination failure due to actual vaccine failure or failure to vaccinate (CIOMS-WHO).
Vaccination failure may be defined based on clinical endpoints or immunological criteria, where
correlates or surrogate markers for disease protection exist. Primary failure (e.g. lack of
seroconversion or sero-protection) needs to be distinguished from secondary failure (waning
immunity) (CIOMS-WHO).

Vaccine failure
Confirmed or suspected vaccine failure.

Suspected clinical vaccine failure

Occurrence of disease in an appropriately and fully vaccinated person, but the disease is not confirmed
to be the specific vaccine-preventable disease, e.g. disease of unknown serotype in a fully vaccinated
person (CIOMS-WHO).

28
Confirmed immunological vaccine failure
Failure of the vaccinated person to develop the accepted marker of protective immune response
after being fully and appropriately vaccinated, as demonstrated by having tested or examined the
vaccinated person at an appropriate time interval after completion of Immunization (CIOMS- WHO)

Suspected immunological vaccine failure

Failure of the vaccinated person to develop the accepted marker of protective immune response
after being fully and appropriately vaccinated, but with the testing or examination of the vaccinated
person done at an inappropriate time interval after completion of Immunization (CIOMS-WHO).
For interpreting what means appropriately vaccinated, consider the explanatory note for
Immunization error-related reaction.

Vaccine pharmacovigilance
The science and activities relating to the detection, assessment, understanding and communication
of adverse events following Immunization and other vaccine- or immunization-related issues, and
to the prevention of untoward effects of the vaccine or Immunization (CIOMS-WHO).

Vaccine product-related reaction

An adverse event following Immunization that is caused or precipitated by a vaccine due to one or
more of the inherent properties of the vaccine product (CIOMS-WHO).

Vaccine quality defect-related reaction

An adverse event following Immunization that is caused or precipitated by a vaccine that is due to
one or more quality defects of the vaccine product including its administration device as provided by
the manufacturer (CIOMS-WHO).
For the purpose of this definition, a vaccine quality defect is defined as any deviation of the vaccine
product as manufactured from its set quality specifications (CIOMS-WHO).

Validated signal
A signal for which the signal validation process has verified that the available documentation
contains sufficient evidence demonstrating the existence of a new potentially causal association,
or a new aspect of a known association, and therefore justifies further analysis of the signal.

Well-established medicinal use products

Medicinal products have been tested and widely used and its efficacy and safety have been well
established. Products were standard of treatment, approved for more than 10 years by stringent
health authorities and agreed with Thai FDA. In such cases, application for marketing authorization
may be based on results from the scientific literature.

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 ABBREVIATIONS
ADR Adverse Drug Reaction
AE Adverse Event
AEFI Adverse Event Following Immunization
ATMP Advance Therapy Medicinal Product
CAPA Corrective Action and Preventive Action
CCDS Company Core Data Sheet
CIOMS Council for International Organization of Medical Sciences
CPPV Contact Person for Pharmacovigilance
DHPC Direct Healthcare Professional Communication
DLP Data Lock Point
EMA European Medicinal Agency
EU European Union
GVP Good Pharmacovigilance Practice
HCP Healthcare Professional
HPVC Health Product Vigilance Center
IBD International Birth Date
ICH International Council for Harmonization
ICSR Individual Case Safety Report
MedDRA Medical Dictionary for Regulatory Activities
MAHs Marketing Authorization Holder
NRA National Regulatory Authority
OTC Over The Counter
PBRER Periodic Benefit-Risk Evaluation Report
PI Package Insert
PSMF Pharmacovigilance System Master File
PSUR Periodic Safety Update Report
PV Pharmacovigilance
PVSS Pharmacovigilance System Summary
QPPV Qualified Person for Pharmacovigilance
RMP Risk Management Plan
RMMs Risk Minimization Measures
RSI Reference Safety Information
SAE Serious Adverse Event
SmPC Summary of Product Characteristics
SOC System Organ Class
Thai FDA Food and Drug Administration of Thailand
US. FDA United States Food and Drug Administration
WHO World Health Organization

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 Chapter 1 Pharmacovigilance System and Quality

WHO defines Pharmacovigilance (PV) as "the research and actions associated with the detection, assessment,
understanding, and prevention of adverse medication effects or other potential drug-related problems."
With the above definition, Pharmacovigilance objectives are to
1. To identify unknown adverse drug reactions
2. To prevent harm from adverse drug reactions
3. To monitor and evaluate the risks and benefits of medicinal products for appropriate action.
4. To promote safe & effective use of medicinal products

PV scope in Thailand
1. PV system with a quality framework in Marketing authorization holders(MAH) and National
Regulatory Authority(NRA)
2. ADR/AEFI reported by healthcare professionals (HCP), consumer, and MAH
3. ADR/AEFI collection and monitoring process by MAH
4. Safety surveillance and signal management process, Periodic Benefit-Risk Evaluation Report
(PBRER)
5. The risk management plan (RMP) includes pharmacovigilance activities and interventions to
identify and mitigate the risks relating to medicinal products, including the intervention program's
effectiveness.
6. Safety communication includes updated Package Insert (PI), Direct Healthcare Professional
Communication (DHPC), or any public media.
A PV system consists of structures, processes, and outcomes.

Scope of products

Medicinal products include new chemical entities, new drugs, generics, biologics, biosimilars, vaccines,
ATMPs, drug and psychotropic substances, and herbal products are in the scope of this chapter.

MAHs and the national regulatory authority should establish an adequate and effective quality system
for PV activities. The quality system is part of the PV system and consists of structures and processes.
It should cover organizational structure, responsibilities, processes, resources management,
compliance management, and record management.

The quality system shall be based on the following activities:

• quality planning
• quality adherence
• quality control and assurance
• quality improvements

31
To ensure the desired level of PV quality, the following framework should guide the design of structures,
processes, and responsibilities.
• The need for safe medicinal products should be established.
• Upper management should endorse & support the PV system with quality standards.
• The people in the organization should support the PV system and engage in continuous quality
improvement.
• Tasks and resource allocation should be structured and organized as processes.
• Continuous monitoring of available evidence for the risk-benefit of medicinal products is
necessary.
• Good cooperation should be established among the MAH, National Regulatory Authorities (NRA),
patient groups, and HCP societies.

The PV quality area should focus on the following key areas to ensure the effective functioning of the
quality system:

• Ensuring that the quality system is documented with proper version control.
• Ensuring that adequate resources are available and employees are provided with appropriate
training.
• Ensuring that suitable and sufficient premises, facilities, and equipment are available.
• Ensuring that compliance management is adequate.
• Ensuring that record management is adequate.
• Reviewing the PV system, including its quality system, at regular intervals.
• Ensuring effective communication mechanisms for safety.
• Identifying and investigating the suspected non-adherence to the quality of PV systems.

Training of personnel for PV

Having sufficient competent, qualified, and well-trained personnel is crucial to achieving the desired PV
quality and outcomes. They must receive both initial and continuous training. Training should cover
necessary qualifications, knowledge of relevant PV requirements, and experience. All employees should
be able to seek guidance on safety concerns. There should be a process to ensure training results in
appropriate comprehension levels.

Non-PV personnel involved in activities with potential PV impact require sufficient training. Among
those activities are, but are not limited to

• clinical trials,
• product complaints,
• call centers,
• medical information,
• sales and marketing,
• regulatory affairs,
• medical affairs,
• market access,
• health-outcome research,

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 • legal affairs,
• audit team.

Appropriate guides in case of urgency, including business continuity, shall be provided to all staff.

Facilities and equipment for PV

Ensuring the necessary quality for the pharmacovigilance processes and their outcomes is closely linked
with having the right facilities and equipment. The facilities should include office space, information
technology, and electronic storage space. It's important to subject critical pharmacovigilance facilities
and equipment to suitable checks, qualifications, version updates, and validation activities to
demonstrate their appropriateness for the intended purpose.

Specific procedures in PV system

To ensure compliance management, the MAHs must have specific quality standard operating
procedures for the following critical PV activities:
• Continuous safety monitoring and benefit-risk evaluation of medicinal products.
• Implementation of risk management plans and evaluation of their effectiveness.
• Timely transmission of ICSRs from any source.
• Signal management.
• Scheduling and preparation of periodic safety update reports.
• Communication of safety concerns with regulatory authorities, patients, and healthcare
professionals.
• Updating product information with new scientific knowledge.
• Implementation of variations to marketing authorizations for safety reasons.
• Establish risk-based business continuity plans with provisions for events that impact staff,
infrastructure, and PV processes.
• Have backup systems for urgent information exchange within the organization,
between organizations sharing PV tasks, and with NRAs.

Record management
The organization should accurately record all PV information and implement a record management
system for all PV documents to ensure proper investigation of safety concerns and traceable decision-
making.

The record management system should have the ability to manage the quality of pharmacovigilance
(PV) data, ensuring completeness, accuracy, and integrity. It should also provide timely access to all
records and facilitate effective internal and external communication. Additionally, the system should
be capable of retaining PV documents for individual medicinal products.

MAHs will establish mechanisms for traceability and follow-up of adverse reaction reports.
The pharmacovigilance system master file (PSMF) must be retained for at least five years after the
Marketing Authorization Holder (MAH) has formally terminated it.

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The data and documents related to each authorized medicinal product should be retained for at least
10 years after the marketing authorization has ended.

For confidentiality, it should be ensured that the fundamental right to privacy is fully and effectively.
Specific measures should be taken as part of a record management system to ensure data security and
confidentiality. This should include restricting authorized personnel's access to documents and
databases.
A timeline for the retention and destruction of structures and processes should be established.

The quality system shall be documented by:

• documents on organizational structures and tasks
• training plans and individual records
• instructions for the compliance management processes.
• instructions on the processes in case of urgency, including business continuity.
• performance indicators to continuously monitor the performance of PV activities.
• reports of quality audits and follow-up corrective action and prevention
• methods of monitoring the efficient operation of the quality system
• record management policy
• records of the facilities and equipment, including functionality checks, qualification, and
validation activities.

Performance and Effectiveness of the PV Quality System

The following processes should be used to monitor the performance and effectiveness of a PV quality
system:
• reviews of the systems
• compliance monitoring
• audit with a regular timeline
• assess the effectiveness of the risk minimization program
• inspections

Qualified person for pharmacovigilance (QPPV) and Contact person for pharmacovigilance
(CPPV) by MAHs

• As part of the PV system, the MAHs should have a Qualified Person for Pharmacovigilance
(QPPV) permanently and continuously available. This individual holds the position of PV
leader within the organization.
o The QPPV should acquire adequate theoretical and practical knowledge to perform
PV activities.
o The QPPV should have skills for the management of PV systems as well as expertise
or access to expertise in relevant areas such as medicine, pharmaceutical sciences as
well as epidemiology and biostatistics.
• The QPPV location should be in Thailand. If the QPPV is located outside of Thailand, the
National Regulatory Authority (NRA) may require a contact person for pharmacovigilance
(CPPV) to be located in Thailand.

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 • The CPPV should have appropriate experience or training in PV to serve as the country contact
person.
• If the QPPV and/or CPPV is not a healthcare professional, he or she should have access to a
medically qualified person.
• MAHs should provide the name and contact details of the QPPV and/or CPPV to NRA, as well
as any changes if applicable. Contact details relating to the QPPV and/or CPPV should be
updated in the pharmacovigilance systems master file (PSMF).
• The duties of the QPPV and/or CPPV should be defined in a job description. The hierarchical
relationship of the QPPV and/or CPPV should be defined in an organizational chart together
with those of other managerial and supervisory staff.
• Each PV system can have only one QPPV. A QPPV may be employed by more than one MAH,
for a shared or for separate PV systems or may fulfil the role of QPPV for more than one PV
system of the same MAH, provided that the QPPV is able to fulfil all obligations.
• MAHs should ensure that the QPPV has sufficient authority to influence the performance of
the quality system and the PV activities of the MAH.
• The QPPV or CPPV (if applicable) should be available and act as the primary PV contact point
for the NRA whenever needed. In the absence of the QPPV or CPPV, the MAHs should prepare
backup staff for both the QPPV and the CPPV (if applicable). The QPPV or CPPV (if applicable)
should ensure that the backup person has all of the information required to perform their
role.

The QPPV ‘s role are proposed as follows (but not limited to):
• To establish an effective PV system to monitor ADR/AEFIs-associated medicinal products.
• To ensure that ADRs and AEFIs are collected and reported in compliance with Thai regulatory
requirements.
• To submit all safety information such as PSUR/PBRER, post-registration study reports, and risk
management plan (RMP)
• To ensure all risk minimization activities (DHPC, package insert, etc) are completed per
commitments.
• To ensure prompt and complete response to NRA's request for additional benefit-risk
information, including sales data of the product.
• To alert the NRA of any emerging safety issue related to medical products
• To manage and share PSMF to NRA if requested.
• The QPPV can delegate specific tasks to appropriate individuals, provided that the QPPV maintains
oversight of the safety profiles of products and the PV quality system. Any delegation should be
documented in the PSMF.

PV tasks subcontracted to a third party.

• PV activities may be subcontracted to third parties. This include the role of the QPPV. The MAHs
shall nevertheless retain full responsibility and the quality and integrity of PV system.
• The MAHs should draft clear subcontracts with third parties, outlining delegation and
responsibilities for each party involved. These should be recorded in the PSMF.

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 Chapter 2 Pharmacovigilance System Master File (PSMF)
The Marketing Authorization Holder (MAH) shall set up a good pharmacovigilance (PV) system to monitor
the benefit-risk balance of their medicinal products. The Pharmacovigilance System Master File (PSMF) is
a working manual for MAHs to guide and manage a good PV system in the organization.

• The PSMF should guide and ensure MAH’s compliance with PV requirements, provide working
system and deficiencies, non-compliance, and risks. It aids the MAHs to implement effective PV
systems.
• The PSMF should be applicable for any medicinal product in Thailand, irrespective of the product
registration procedure or marketing status (except for herbal products, cosmetic products, and
veterinary products).
• National Regulatory Authorities (NRAs) may request the MAHs to submit the PSMF prior to or
during a PV inspection, or in special circumstances, such as conditional marketing authorization
of medicinal products.
• The content of PSMF should provide an overview of safety management for medicinal products
authorized in Thailand. Additional regional and/or global information or activities may be
included as necessary to reflect the overall PV system of the MAHs.
• The PSMF should provide a detailed description of the PV system for multiple medicinal products
of the MAH. The MAHs may apply separate PV systems for different product categories, and each
system should be described in a separate PSMF. These files should collectively cover all the
approved medicinal products of the MAHs.
• In case one MAHs may establish more than one PV system, e.g., specific systems for different
types of products (vaccines, consumer health, etc.), or the PV system may include products from
more than one MAHs. In either case, a single and specific PSMF should describe each system.
• A single QPPV should be appointed to be responsible for the establishment and maintenance of
the PV system described in the PSMF.
• When several MAHs share a PV system, each MAHs is responsible for ensuring that a PSMF exists
to describe the PV system applicable to his products.
• The PSMF content should be updated regularly and all changes should be recorded.
• However, any changes in these situations should be notified to the NRAs within 30 days of being
aware of them.
o changes in QPPV, CPPV and the back-up staff & contact details
o changes in PV safety database
o changes in PV service provider, organizational changes (such as mergers or acquisition)

The PSMF Content: 9 sections

1. Person responsible for pharmacovigilance (QPPV)

o QPPV, CCPV (if applicable) and back up staff curriculum vitae & contact detail
o QPPV, CCPV (if applicable) and back up staff responsibilities for the PV system
o CCPV should be proposed in case QPPV is not located in Thailand.
o Back-up arrangements in case of absence of QPPV and/or CCPV

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 o A list of tasks delegated to team members or need to access to a medically qualified
person if applicable.
o If the QPPV is employed by a third party, the name of the company the QPPV works for
should be provided.

2. MAHs ‘s organizational structure

o The MAHs organizational structure (chart) related to the PV system should be provided,
including all involved departments and between organizations (co-marketing) &
subcontract third parties.
o The department(s) that handle PV functions included ICSR collection, evaluation,
database case entry, PSUR production, signal detection and analysis, RMP, pre- and post-
authorization study, and product safety variations.
o The list of service providers
▪ medical information,
▪ auditors,
▪ patient support program providers,
▪ study data management,
▪ distributors, licensing partners, co-marketing partners,
▪ service provider of computer systems
o Individual contractual agreements should be available on request during inspection and
audit

3. Sources of safety data

o The description of the units for safety data collection, medical information, and a list
describing the country and nature of the activity and providing a contact staff and address
for the site. The list may be in the Annexes.
o The source of safety data should focus on activities in Thailand; however, overall or global
activities may be added as needed.
o A flow diagram & timeframe may be applied to describe the process for ICSRs collection
and reporting to the NRA with the departments and/or third parties involved.
o List of studies, registries, surveillance or support programs sponsored by the MAH
▪ Interventional and non-interventional studies/programs by product(s) together
with study objective, study status with ongoing or completed studies in the last
two years (List is provided in the PSMF Annexes).
4. Computerized systems and databases
o The location, functionality, and operational responsibility for computerized systems
and databases for PV systems should be described
o If multiple computerized systems/databases are used, the applicability to PV work
should be described clearly
o The validation of computer system functionality should also be described; the change
control, nature of testing, back-up procedures and electronic data repositories vital
to PV compliance should be included

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 o For paper-based systems (where an electronic system may only be used for expedited
submission of ICSRs), the management of the data, and mechanisms used to assure
the integrity and accessibility of the safety data should be described
5. PV processes
o All PV procedures for PV working systems, including standard operating
procedures(SOP), policy, and manuals in Thailand and globally ( if applicable), should
be written clearly.
o A description of the process, workflow, data handling, and records for the PV
performance, covering the following aspects shall be included
a. Continuous monitoring of risk-benefit profiles, including signal generation,
detection, evaluation, and decision-making for appropriate measures.
b. Risk Management Plan (RMP) and monitoring of the outcome of risk minimization
measures
c. Individual case safety report (ICSR) collection, collation, follow-up, assessment,
and reporting
d. Periodic Benefit risk Safety Report (PBRER) scheduling, production, and
submission, if applicable
e. Communication of safety concerns to consumers, HCP, and the NRA
f. Implementation of safety variations to the summary of product characteristics
(SmPC) and patient information leaflets
g. Interfaces with others include, but are not limited to,
• the roles and responsibilities of the QPPV
• responding to NRA requests for information
• literature searching
• safety database change control
• safety data exchange agreements
• safety data archiving
• PV auditing
• quality control and training
o The list, located in the Annexes, should comprise the procedural document reference
number, title, effective date, and document type.
o Procedures belonging to service providers and other third parties should be clearly
identified.

6. PV performance
o PV performance should be monitored, including compliance of the main outputs in
Thailand. However global and other countries may be added as needed.
o As a minimum, the description of the monitoring methods applied should be included.
• Include figures/graphs in the annex to show timely reports over the past year for
assessing correct ICSR reporting.
• Overview of PBRER submission timeliness and present in figures in the annex for
compliance assessment.(if applicable)
• Analyze and track safety variation submissions of MAHs vs regulatory deadlines,
including pending submissions.

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 • If applicable, provide an overview of compliance with post-authorization obligations,
commitments, and any special conditions.
• Targets for PV performance should be specified, and a list of performance indicators
with actual results provided in the PSMF Annex.
7. Quality system of PV
o Document and Record Control
• Describe the archiving of electronic and/or hardcopy of the PSMF, as well as an
overview of the procedures applied to other quality systems and PV records and
documents
o Procedural documents
• Describe the types of documents (standard operating procedures, work instructions,
etc.), their applicability at the country or global level within the organization or third
party, and the controls of accessibility, implementation, and maintenance.
o Training
• Describe the resource management for PV activities with the number of staff (full-
time equivalents)
• Explain the training concept development and tools for all PV staff at all sites
• Non-PV Staff who may receive safety reports should be included for training
appropriately.
o Auditing
• Describe quality assurance auditing plan & report for PV system
• Provide a list of the audit plans and schedules, timelines, and previous results for the
last 5 years in the annex
• Provide an audit report with significant findings ( major or critical level)
• The audit report with corrective action preventative action(CAPA) should be
documented within the quality system
• Audits with unresolved notes should be listed in the annex until it is implemented and
resolved. Amendment or removal of the notes must be recorded in the logbook.
• As a basis for audit or inspection, the process for recording, managing, and resolving
deviations from the quality system should be described.
• List of deviations report, date, and procedure concerned should be documented until
resolved
8. Logbook; Change control, versions, and archiving
• Changes should include at least the date, the person responsible for the change, and
the nature of the change
• Changes to the PV safety database(s), the validation status of the new database as
well as information about transferred or migrated data;
• Changes in PV service providers, especially major contractual arrangements of safety
reporting;
• Organisational changes, such as takeovers, mergers, the sites at which PV is
conducted, or the delegation/transfer of PSMF management.
• Changes to the PSMF should be described and recorded in the logbook, such that a
history of changes is available (specify the date and the nature of the change),
• The previous versions of such content may be managed outside of the PSMF content
itself, provided that the history of changes is maintained and available to the NRA on
request.

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 o MAHs should have document control procedures in place to govern the maintenance
of the PSMF. As a basis for audits and inspections, the PSMF provides a description
of the PV system at the current time, but the functioning and scope of the PV system
in the past may need to be understood.

9. Annex to the PSMF

• Where PV systems are shared among MAHs, all products in that PV system should be
included in the list. The product lists may be presented separately, organized per
MAH. Alternatively, a single list may be used, which is supplemented with the name
of the MAH(s) for each product, or a separate note can be included to describe the
product(s) and the MAH(s) covered

• Blank content pages of annexes are not required. Still, name any provided Annexes
according to the format. For example, Annex E shouldn't be renamed to Annex D if
there's no Annex related to computerized systems. Mark Annex D as 'unused' in the
index instead.
o Annex A QPPV /CPPV
▪ The list of tasks for the QPPV/CPPV or the applicable procedural document
▪ The curriculum vitae of the QPPV/CPPV and associated documents
▪ Contact details supplementary if appropriate
o Annex B The Organisational Structure
▪ The lists of contracts and agreements
o Annex C Sources of safety data
▪ Lists associated with the description of sources of safety data e.g. affiliates and
third party contacts
o Annex D Computerised systems and Databases
o Annex E PV Process, and written procedures
▪ Lists of procedural documents
o Annex F PV System Performance
▪ Lists of performance indicators
▪ Current results of performance assessment in relation to the indicators
o Annex G Quality System
▪ Audit schedules
▪ List of audits conducted and completed
o Annex H Products,
▪ The list of medicinal products covered by the PV system registered in Thailand
(regardless of current status) should be presented in a table with the following
information:
− Active ingredient
− Product name (the registered name)
− Product registration number in Thailand
− Product registered category (e.g., new chemical drug, generics , biologics,
biosimilar, vaccine ATMP etc )
− Drug class (dangerous drug , special control drug , dangerous drug with
exemption , household remedy ,narcotic drug, psychotropic drug-
substances etc )

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 − Product registration status (e.g. authorization approval, emergency use
authorization, conditional marketing authorization, donation
authorization, etc )
− Marketing status
− A list of products with additional risk minimization activities ( if applicable
)
▪ Where MAHs has multiple PV systems or third-party agreements exist to
delegate the system, a separately list of products per PV system should be
arranged.

o Annex I Document and Record Control

▪ Logbook
▪ Documentation of the history of changes for Annex contents, indexed according
to the Annexes A-H and their content if not provided within the relevant annex
itself

PSMF presentation
o The Thailand PSMF may be written in English or Thai language, indexed in a manner
consistent with the headings described.
o The Thailand PSMF may be in an electronic or a hard copy form. The electronic form of PSMF
should be made available as a hard copy upon request from the NRA.
o The PSMF should be legible, complete, and provided in a manner that ensures all
documentation is accessible and allows full traceability of changes.

The cover page of PSMF should include:

o The name of the MAH
o The name of any other subsidiary companies related to this PV system ( if applicable )
o The name of QPPV and or CPPV (if applicable)
o The third party company name of the relevant QPPV and CCPV (if applicable)
o The list of PSMF for the MAHs (if more than one PV system)
o The date of prepared/last update and version number

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 Chapter 3 Inspection

This chapter provides guidance on the planning, conduct, reporting, and follow-up of pharmacovigilance
(PV) inspections in Thailand, as well as an overview of the various parties involved.
National regulatory authorities (NRA) should conduct PV inspections to fulfill MAHs’ PV obligations in
order to determine that marketing authorization holders (MAH) comply with PV obligations established
in Thailand and facilitate compliance.

The objectives of pharmacovigilance inspections are:

• to determine that the MAHs has personnel, systems, and facilities in place to meet their PV obligations;
• to identify, record, and address non-compliance which may pose a risk to public health;
• to use the inspection results as a basis for enforcement action if necessary.

Inspection types
1. System and product-related inspections
• PV system inspections are designed to review the procedures, systems, personnel, and
facilities in place and determine their compliance with regulatory pharmacovigilance
obligations. This may include some products for demonstatrte the PV operation.
• Product-related PV inspections are primarily focused on product-related PV issues, including
product-specific activities and documentation, rather than a general system review. However,
some aspects of the general system may still be examined as part of a product-related
inspection.
2. Routine and “for-cause” pharmacovigilance inspections
• Routine PV inspections are inspections scheduled in advance as part of inspection programs.
There is no specific trigger to initiate these inspections, although a risk-based approach to
optimize supervisory activities should be implemented. These inspections are usually system
inspections, but one or more specific products may be selected as examples to verify the
implementation of the system and to provide practical evidence of its functioning and
compliance.
• For-cause PV inspections are undertaken when a trigger is recognized, and an inspection is
considered an appropriate way to examine the issues. For cause inspections are more likely to
focus on specific PV processes or to include an examination of identified compliance issues and
their impact for a specific product. However, full system inspections may also be performed
resulting from a trigger.
The triggers listed below are identified for the for-cause PV inspection.
o risk-benefit balance of the product: −
▪ change in the risk-benefit balance
▪ delays or failure to identify or communicate a risk
▪ communication of PV information to the public without giving prior or
simultaneous notification to the NRA
▪ non-compliance or product safety issues identified during the monitoring of PV
activities by the NRA
▪ suspension or product withdrawal with no advance notice to NRA
o reporting obligations (expedited and periodic)
▪ delays or omissions in reporting

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 ▪ poor quality or incomplete reports
▪ inconsistencies between reports and other information sources
o requests from NRA
▪ failure to provide the requested information within the NRA specific deadline.
▪ poor quality or inadequate data to fulfil NRA information request.
o fulfilment of commitments
▪ concerns about the fulfilment of risk management plan (RMP) commitments
▪ delays or failure to carry out specific obligations relating to the monitoring of
product safety during the marketing authorization
▪ poor quality of reports.
o prior or other Inspections
▪ delays in the implementation or inappropriate implementation of corrective
and preventive actions (CAPA)
▪ information such as non-compliance or product safety issues from other types
of inspections (All GxP; GCP, GMP, GLP and GDP)
▪ inspection information received from other NRA, which may relate to non-
compliance issues
o others:
▪ concerns following review of the Pharmacovigilance system master file (PSMF);
▪ non-compliance information received from other regulatory authorities
3. Pre and Post-authorization inspections
• Pre-authorization inspections are inspections performed before a marketing authorization is
granted. These inspections are to examine the existing or proposed PV system as it has been
described by the applicant in support of the marketing authorization application. In most cases, a
risk assessment based on a combination of product-specific and system-related issues should be
performed before a pre-authorization PV inspection is requested.
Pre-authorization inspections are not mandatory, but may be requested in specific circumstances
include;
o MAHs has not previously operated a PV system in Thailand or is in the process of
establishing a new PV system
o poor history of non-compliance information from other NRA
o due to product-specific safety concerns
▪ to implement product specific risk-minimization activities
▪ to meet specific safety conditions which may be imposed
▪ to manage routine PV for the product of concern (anticipated significant increase
in adverse reaction reports when compared to previous products)
If the outcome of the pre-authorization inspection raises concerns about the MAHs ’s ability to
comply with the requirements, the following recommendations may be considered:
o non approval of the marketing authorization.
o re-inspection prior to approval of the marketing authorization
o granting of the marketing authorization with the recommendation to perform an early
post-authorization PV inspection.
o imposition of safety conditions to the marketing authorization

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 • Post -authorization inspections are inspections performed after a marketing authorization is
granted and are intended to examine whether the MAHs complies with its PV obligations.

4. Announced and unannounced inspections

• It is anticipated that most inspections will be announced in advance to the inspected party, to
ensure the availability of relevant individuals for the inspection.
• However, it may conduct unannounced inspections or to announce an inspection at short notice
when the inspection is conducted in a short timeframe due to urgent safety reasons.

5. Remote and on-site inspections

• Remote Inspections performed by inspectors remote from the firms employed by the MAH.
Communication technologies include live or real-time streaming video, screen-sharing, or other
means of real-time communication. This approach may also be used when an on-site inspection
would be difficult logistically due to exceptional circumstances.
• Onsite inspections at firm of MAH. This is based on the risk assessment, size of the company, and
complexity of the PV system & process.

Inspection scope

• The scope will depend on the inspection objectives, the result of previous inspections and
whether it is a system or product-related inspection.
• Additional data should be requested in advance of an inspection in order to select appropriate
sites or clarify aspects of the PV system
• The following elements should be considered for the inspection scope:
o information in the pharmacovigilance system master file (PSMF)
o compliance data &report from NRA and data quality audits

1. Scope of routine pharmacovigilance inspections should examine compliance with Thailand

legislation and guidance including the following elements:
• individual case safety reports (ICSRs)
o collecting, receiving, and exchanging reports
o assessment
o follow-up and outcome recording
o reporting and timeliness
o record and archiving
• periodic benefit risk evaluation report (PBRER), (as applicable):
o completeness and accuracy of the data
o addressing safety topics
o formatting
o timeliness of submissions
• ongoing safety evaluation
o signal detection
o analysis
o follow-up actions
o implementation of the RMP, or other commitments
o timely response to specific NRA requests for data
o implementation safety communications

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 • interventional and non-interventional clinical trials:
o reporting suspected unexpected serious adverse reactions (SUSARs)
o receiving, recording, and assessing cases from trials
o submission of study results
o selection of reference safety information (RSI) included investigator brochures and
patient information on safety
o inclusion of study data in ongoing safety evaluation
• pharmacovigilance system:
o QPPV roles and responsibilities
o the roles and responsibilities of the MAHs in the PV system
o the PSMF
o training of staff
o quality system and quality assurance processes
o computerized systems
o PV contracts and agreements with all parties

2. Scope of for-cause inspections will depend on the specific triggers. Some, but not all of the
elements listed may be relevant:
a. QPPV involvement and awareness of product-specific issues;
b. in-depth examination of processes, decision-making, communications, and actions
relating to a specific trigger and/or product.

Inspection process
1. Preparation step
i. It involves planning to ensure inspection objectives are achieved. PV inspections
should be planned, coordinated, conducted, reported on, followed-up and
documented.
1. Resource allocation
• Trained and experienced inspector(s) should be appointed for an inspection.
2. Announcing the inspection
• NRAs should the right to inspect at any time. In some cases, an inspection may be
performed without prior notice. This could arise, for example, in the conduct of a “for
cause” inspection to investigate an immediate public health or compliance concern.
• However, routine practice is for advance notice of the intent to inspect a PV system
to be given to MAH. The 6-8 weeks of notice should be sufficient for MAHs to enable
logistical arrangements and review of relevant data.
• Announcement could include name of the inspector(s), MAH, the objectives and type
of the inspection and address of the inspection site(s). Additional information,
including specific product authorizations, to be reviewed if applicable.
• The announcement should be issued to the relevant contact person, requesting
confirmation of the inspected entity’s availability, and that access to all required
documents/databases will be provided. The timeline and method of submission of
documentation should be clearly defined for the inspected entity.

2. Conduct of inspection
Information to fulfil the inspection can be collected by, for example:
• review of relevant documents

45
 • examination of computer systems
• conduct of interviews
• review of internal and external communication e.g., logbooks, registries, communication
with authorities etc.
• Opening meeting
An opening meeting must take place between the inspection team and the company being
inspected. The chair of the meeting should be the lead inspector. The purpose of the opening
meeting is to:
• introduce the inspection team
• explain the regulatory framework for the inspection
• provide scope and the objectives of the inspection
• clarify logistics, timeframes and other references
• introduce the MAHs representatives attending the inspection
• allow the company to present an overview of the PV system
• Review of documentation, processes, and systems
The documents and processes to be reviewed during an inspection will depend on the type, scope,
and focus of the inspection, for example a “for cause” inspection may focus on particular issues
of concern.
• Inspection observations
All inspection observations should be documented. If appropriate, copies should be made of
records containing inconsistencies or illustrating non-compliance.
• Closing meeting with the inspected entity
The purpose of the closing meeting is to:
• explain the finding grading, timelines for distribution of the report, response and follow-
up measures
• provide the inspected party to correct misconceptions and misunderstandings in
response to the findings.
• present a summary of the inspection findings with classification below.
Classification of inspection findings
1. Critical: a deficiency in PV systems, practices or processes that adversely affects the rights,
safety or well-being of patients or that poses a potential risk to public health or that
represents a serious violation of applicable legislation and guidelines.
2. Major: a deficiency in PV systems, practices or processes that could potentially adversely
affect the rights, safety or well-being of patients or that could potentially pose a risk to
public health or that represents a violation of applicable legislation and guidelines.
3. Minor: a deficiency in PV systems, practices or processes that would not be expected to
adversely affect the rights, safety or well-being of patients

3. Report of inspection
• The report should be issued in 30 working days after the end of the inspection (the time
is calculated from the last day of the last inspection or from when the last post-inspection
document has been received).
• Corrective and preventive actions (CAPA) should be provided by the MAHs within 30
working days after receiving the report
• When the CAPA proposed by the MAHs is acceptable, the inspection may be closed.

4. Record management and archiving

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 PV systems inspections should preferably be maintained for as long as the PV system is in
place and for at least 10 years after the system ceases to exist.

Role of MAHs

MAHs should always be ready for regulatory inspections and be aware of these activities during the PV
inspection.
• to ensure that the sites selected agree for PV inspection
• to make available to the inspectors any information and/or documentation required for the
preparation of the inspection within the deadline given or during the conduct of the inspection
• to ensure that relevant PV staff are present and available for interviews or clarification
• to ensure that relevant PV data is accessible
• to ensure that appropriate and timely corrective and preventive action plans are implemented
to address findings

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 Chapter 4 Audits
In general, an audit is a systematic, disciplined, independent, and documented process for gathering
evidence and objectively evaluating the evidence to determine the extent to which the audit criteria are
met, thereby contributing to improving risk management, control, and governance processes.

Pharmacovigilance (PV) audit activities should verify the appropriateness and effectiveness of a PV
system's implementation and operation, including its quality system for PV activities, through examination
and evaluation of objective evidence.

The audit principles follow internationally recognized auditing standards issued by relevant international
auditing standardization organizations such as The Institute of Internal Auditors (IIA) (www.theiia.org),
the International Organization for Standardization (ISO) (www.iso.org), and others.

All organizations involved in PV activities should perform audits of their PV systems in a regular manner
to ensure their PV quality commitment.

Level of audit plan

The risk-based approach is applied for PV audits to focus on the high-risk areas in the PV system of
organizations, including its quality system. Risk can be assessed at the following levels:
• strategic level (long-term plan)
• tactical level (audit program)
• operational plan (fieldwork & report)

1. Strategic level
The audit strategy is a high-level audit plan for a period of 2-5 years. The audit strategy is
to outline the risk areas, the audit topics, and the methods and assumptions (risk
assessment) for the proposed audit program. The audit strategy should include the
governance, risk management, and internal controls of the PV system including:
• all PV processes
• the PV quality system
• interactions with others
• PV activities conducted by affiliated or third parties

These are examples for the purposes of a risk assessment:

• changes to legislation and guidance
• major change in organization
• change in key managerial function(s)
• availability & turnover of PV staff
• any changes since the last audit
• first medicinal product on the market
• specific risk minimization or safety conditional implementation
• outcome of previous audits
• identified gaps relating to the specific area
• other organizational changes (information technology function)

48
 • criticality process including PV activities impact on public health for national regulatory
authority (NRA) or PV activities performed by third party or affiliates for marketing
authorization holders (MAH)
• compliance with legislation and guidance, including metrics on PV activities, complaints,
external audits, or inspections.

2. Tactical level
This is a set of audit programs for a year. The audit program should include the audit type,
scope, objectives, timing, and periodicity. The audit program should be based on risk
assessment and focus on:
• PV quality system
• critical PV processes
• key control systems
• high-risk areas (after controls are put in place)

3. Operational level
1. Planning and fieldwork
The organization should have procedures for planning and conduct of audits. The auditor
identifies and assesses the risk to employ the appropriate risk-based sampling and testing
methods, documenting the audit approach in an audit plan
2. Reporting
▪ The findings should be documented in an audit report and should be
communicated to the auditee and upper management in a timely manner.
▪ Audit findings should be graded to indicate their relative criticality to risks
impacting the PV system, processes, and parts of processes.

The grading system of audit finding are defined below

i. Critical: a fundamental weakness in > 1 PV process or practice that adversely
affects the whole PV system and/or the rights, safety, or well-being of patients or
that poses a potential risk to public health and/or represents a serious violation
of applicable regulatory requirements.
ii. Major: a significant weakness in >1 PV process or practice, or a fundamental
weakness in part of >1 PV process or practice that is detrimental to the whole
process and/or could potentially adversely affect the rights, safety, or well-being
of patients and/or could potentially pose a risk to public health and/or represents
a violation of applicable regulatory requirements which is however not
considered serious.
iii. Minor: a weakness in the part of >1 PV processes or practices that is not expected
to adversely affect the whole pharmacovigilance system or process and/or the
rights, safety, or well-being of patients.

Actions and follow-up of audits

• Actions within a reasonable timeframe and issues that need to be urgently communicated with
relevant parties should align with the relative risk to the PV system.
• Corrective action and preventive actions (CAPA) to address critical and major issues should be
prioritized.

49
 • The upper management of the organization should have a mechanism to adequately address the
issues arising from PV audits.
• Actions should include root cause analysis and impact analysis of audit findings and preparation
of CAPA appropriately and effectively.
• Evidence of completion of actions needs to be recorded.

Competence of auditors
• PV audit activities should be independent. The organization should ensure this independence and
objectivity in a structured manner and document this.
• Auditors should be free from interference in determining the auditing scope, performing PV
audits, and communicating audit results.
• The main reporting line of the internal auditor should be to the upper management.
• Auditors can consult with technical experts and personnel involved in PV processes. However,
auditors should have an unbiased attitude to perform audit work without significant quality
compromises.
• The organization may use an outsourced audit service provider to perform PV audits.
• Qualifications, skills, and experience of auditors should be obtained through a combination of
education, work experience, and training and, as a team, should cover knowledge, skills, and
abilities in:
i. Audit principles, procedures, and techniques
ii. Laws, regulations, and others relevant to PV
iii. PV activities, processes, and system(s)
iv. Management system(s)
v. Organizational system(s)

Quality of audit activities

• Evaluation of audit work can be evaluated by periodic assessment of all audit activities, auditee
feedback, and self-assessment.

50
 Chapter 5 Safety Reporting Requirement

Pharmacovigilance (PV) is defined by the World Health Organization (WHO) as “the science and activities
relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-
related problems.” It is an arm of patient care with the ultimate endpoint to improve patient care and
safety. Another motivation is to reduce the substantial financial burden of adverse reactions upon the
healthcare sector and society.

Safety collection is a crucial aspect of pharmacovigilance (PV) activities. PV methods for data collection
can be classified as passive or active.
• Passive pharmacovigilance: No active measures are taken to look for adverse reactions other than
encouraging healthcare professionals and others to report safety concerns. Reporting is entirely
dependent on the reporters. It is commonly called “spontaneous” or “voluntary” reporting. For example,
spontaneous reporting, intensified /stimulated reporting system, and targeted spontaneous reporting
(TSR) with no active measures.
• Active (or Proactive) pharmacovigilance: Active measures are taken to monitor adverse events.
This is actively organized to follow up after treatment, and the events can be obtained by asking
patients directly or screening medical records. The most comprehensive method is cohort event
monitoring (CEM). The other methods include the use of a registry, record linkage, and screening of
laboratory reports in medical records.

All parties involved in pharmacovigilance, including the national regulatory authority (NRA) and marketing
authorization holders (MAH), must implement appropriate measures to identify signals or risks associated
with the use of medicinal products and report their findings in a timely manner. This helps to improve
patient care and public health by promoting the safe, rational, and more effective (including cost-
effective) use of medicinal products.

Pharmacovigilance in drug regulation

Before being marketed, medical products shall obtain marketing authorization from NRA. Sufficient
evidence is required to demonstrate that the product is of high quality, effective, and safe for the intended
use. However, due to the limitations of the pre-registration studies, rare serious adverse events may not
be identified at the time of approval.

It is generally accepted that PV has become an essential component of drug regulation to monitor the
safety of medicinal products in the post-marketing phase. The stronger the national PV system, the more
reasonable the regulatory decision. Therefore, most countries worldwide, including Thailand, will have
such a system in place. As the safety reporting has already adopted and required by Thailand regulation,
so this chapter will summarize and update all requirement according to Thailand regulation.

As the safety reporting is required by Thai FDA. This chapter will guide how to collect, and report of
emerging safety issues or adverse events (AE) of the product authorized in Thailand. This also intends to
improve effectiveness, standardize the reporting system, and cover all safety issues.

1 Legal basis for safety reporting

The law and regulation related safety reporting are published in accordance with the following Act.
• Drugs Act, 1967 (amended in the years 1975, 1979, 1984, 1987, and 2019)
• Act Promulgating a Narcotic Code, 2021
• Herbal Product Act, 2019
• Communicable Diseases Act, B 2015

51
 2 Confidentiality
All organizations involved in PV including NRA shall maintain strict confidentiality concerning the identity
of patients and reporters, which is aligned with The Personal Data Protection Act 2019 (“PDPA”) of
Thailand.
In this context, it should be ensured that the fundamental right to personal data protection is fully and
effectively guaranteed in all PV activities in conformity with legal provisions. The purpose of safeguarding
public health constitutes a substantial public interest and consequently the processing of personal data
should be justified if identifiable personal data are processed only where necessary and only where the
parties involved assess this necessity at every stage of the PV process.

3 Definition
The definitions provided shall be applied for the purpose of this chapter.
1) Adverse Event (AE)
a. Any untoward medical occurrence in a patient or clinical trial subject administered a
medicinal product that does not necessarily have a causal relationship with this
treatment.
b. An AE can, therefore, be any unfavorable and unintended sign (e.g., an abnormal
laboratory finding), symptom, or disease temporally associated with the use of a
medicinal product, whether or not considered related to the medicinal product.

2) Adverse reaction; synonyms: Adverse Drug Reaction (ADR)

Adverse drug reactions, as established by regional regulations, guidance, and practices, concern
noxious and unintended responses to a medicinal product. The phrase “responses to a medicinal
product” means that a causal relationship between a medicinal product and an adverse event is
at least a reasonable possibility (refer to ICH E2A).
A reaction, in contrast to an event, is characterized by the fact that a causal relationship between
the drug and the occurrence is suspected. For regulatory reporting purposes, if an event is
spontaneously reported, even if the relationship is unknown or unstated, it meets the definition
of an adverse drug reaction. (refer to ICH-E2D) Therefore all spontaneous reports notified by
healthcare professionals or consumers are considered suspected adverse reactions, since they
convey the suspicions of the primary sources, unless the primary source specifically state that
they believe the event to be unrelated or that a causal relationship can be excluded.

This includes adverse reactions that arise from using within or outside the terms of the marketing
authorization or from occupational exposure, including overdose, off-label use, misuse, abuse,
and medication error.

3) Serious AE/ADR
An adverse event or reaction which
• results in death
• is life-threatening
• requires in-patient hospitalization or prolongation of existing hospitalization
• results in persistent or significant disability or incapacity
• is a congenital anomaly/birth defect

52
 • is a medically important event or reaction. An important medical event or reaction might not
be immediately life-threatening or result in death or hospitalization but might jeopardize the
patient or might require intervention to prevent one of the other outcomes listed in the
definition above.
o Examples of such events are: intensive treatment in an emergency room or at home
for allergic bronchospasm, blood dyscrasias or convulsions that do not result in
hospitalization or the development of drug dependency or drug abuse.

4) Unexpected ADR
An adverse reaction, the nature, severity, or outcome of which is not consistent with the summary
of product characteristics. In the context of a clinical trial, an unexpected serious adverse reaction
means a serious adverse reaction, the nature, severity or outcome of which is not consistent with
the reference safety information (e.g. the investigator’s brochure for an unauthorized
investigational product or the summary of product characteristics for an authorized product)
An expected ADR with result in death should be considered unexpected unless the local/regional
product labeling specifically states that the ADR might be associated with a fatal outcome.
When an MAHs is uncertain whether an ADR is expected or unexpected, the ADR should be
treated as unexpected.

5) Individual Case Safety Report (ICSR)

This refers to the format and content for reporting one or several adverse events or reactions
that occur in a single patient at a specific time.

4 Scope of reporting
4.1 The scope of event or reaction of concern includes the following domains;
• Adverse event(AE) , Adverse drug reaction (ADR), or Adverse reaction
• Other product-related problems, e.g.,
• Lack of efficacy
• Misuse, abuse, off-label use
• Medication error, Immunization error-related reactions
• Overdose
• Interaction with medicinal or non-medicinal products
• Counterfeit or substandard medicines, including vaccine quality defect related reaction
• Pregnancy and lactation exposure and outcomes.
• Occupational exposure
• Suicidal attempt
• Accidental use
• Coincident (vaccines)

4.2 Type of products for monitoring and reporting included products with marketing
authorized license approval and license exemption ;
• Medicinal products for human use, including biological products and vaccines.
• Narcotic drug and psychotropic substances
• Herbal products for human use include
o Herbal medicines;
o Herbal health supplements, including health supplements and cosmeceutical products

Remarks; Investigational new drug (IND) is out of scope of this guidance

53
 5 Reporter
All manufacturers and importers of any products (section 4.2) have to bear primarily for the safety of
their products. They are required to monitor and report any product safety issues (section 4.1) that
arise locally or internationally to HPVC, the Thai FDA in accordance with the safety reporting
regulation of medicinal products. These include.
• All MAHs who have marketing authorization licenses for any products (section 4.2) in Thailand
• MAHs who import any medicinal products under the donation authorization pathway
• Public organizations/institutes who import or produce any medicinal products under the
exemption authorization pathway in accordance with Drugs Act, 1967 section 13
❖ Ministry/department that has duty to treat /prevent diseases, such as Department of Disease
Control (DDC)
❖ Government Pharmaceutical Organization (GPO)
❖ Thai Red Cross
❖ Public hospitals

6 What to report
All reporters in section 5 shall submit ICSRs, and monitor AE/ADR, other ADR/AE related product problem
(section 4.1), and emerging safety issues (new safety information) of the any products (section 4.2) to
HPVC, Thai FDA, in accordance with the reporting requirement.

6.1 Individual Case Safety Reports (ICSRs)

6.1.1 sources of reports
There are two types of safety reports distinguished in the post-authorization phase, which are based on
the source of reports, including;
a) Unsolicited reports: the reports are derived from non-organized data collection schemes which
include spontaneous reports, literature reports, information from the internet or digital media,
or reports from non-medical sources.
b) Solicited report: reports are derived from an organized data collection schemes which include
clinical trials, non-interventional studies, registries, post-approval named patient use programs,
patient support and disease management programs, surveys of patients or healthcare
professionals, compassionate use program, or information gathering on efficacy or product
compliant.

6.1.2 General requirements

All AEs that occurred with any products (section 4.2) either in Thailand or outside Thailand are required
to be submitted to HPVC, the Thai FDA, if they comply with the details in Table 1.

The HPVC form 1 is a standard form for ICSR reporting in Thailand. However, no matter what form or
format is used, it is important that certain basic data elements, when available, be included with any
ICSR. It is recommended that the Medical Dictionary for Regulatory Activities (MedDRA) be used for
coding medical information.

(https://hpvcth.fda.moph.go.th/hpvc-form-1-
%E0%B9%81%E0%B8%9A%E0%B8%9A%E0%B8%A3%E0%B8%B2%E0%B8%A2%E0%B8%87%E0%B8%B2
%E0%B8%99%E0%B9%80%E0%B8%AB%E0%B8%95%E0%B8%B8%E0%B8%81%E0%B8%B2%E0%B8%A3
%E0%B8%93%E0%B9%8C%E0%B9%84%E0%B8%A1-7/?download=17818)

Electronic submission of ICSRs using the HPVC adverse event reporting system is required for all MAHs.
Additional information should be provided in the attachment to the system, if applicable.

54
(https://hpvcth.fda.moph.go.th/hpvc-form-1-แบบรายงานเหตุการณ์ ไม-8/)

table 1 General requirements for reporting of ICSRs 1

Origin Type of Products Time frame
events/reactions
Initial report Follow up report
(after first (after received additional
acknowledgement) information)
Thailand - Unexpected • Medicinal products for
serious AE result human use, including • Notify within 1 • Submit a report within
in death biological products business day and 15 calendar days
and vaccines. submit a complete
• Narcotic drugs and report within 7
psychotropic calendar days.
substances
• Herbal products

- Expected serious • Notify within 7

AE result in calendar days and • Submit a report within
death submit a complete 15 calendar days
report within 8
calendar days. (no
later than 15 calendar
days of initial receipt
of the information by
the reporter).

- Other serious AE • Submit a report with • Submit a report within

15 calendar days. 30 calendar days

• Non-serious • medicinal products for • Submit report within 2 • Submit a report within
AE human use including, months 30 calendar days
biological products
and narcotic drugs
and psychotropic
substances which
having less than 7
years of use in
Thailand.
• Vaccine (AEFI)
• Herbal products based
on Thai FDA
notification

Other • Serious AE • all type of products • Notify within 7 • Submit a report within
countries2 - unexpected or (above) that produced calendar days and 15 calendar days
expected result or authorized from submit a complete
in death Thailand report within 8
calendar days. (no
later than 15 calendar
days of initial receipt
of the information by
- Other serious AE the reporter). • Submit a report within
• Submit a report within 30 calendar days
15 calendar days

55
 1. exclude the investigational new drug (IND)
2. this applies for any patients who taking medicinal products for human use that produced or authorized from Thailand
6.2 Emerging safety issue/New safety information
This refers to a safety issue considered by an MAHs to require urgent attention by the NRA because of the
potential major impact on the risk-benefit balance of the medicinal product on patients’ or public health
and the potential need for prompt regulatory action and communication to patients and healthcare
professionals. Examples include:
• Major safety issues identified in the context of ongoing or newly completed studies, e.g., an
unexpectedly increased rate of fatal or life-threatening AEs
• Major safety issues/signal identified through the spontaneous reporting system or publications in
the scientific literature, which may lead to considering a contraindication, a restriction of the use
of a medicinal product, or its withdrawal from the market
• Major safety-related regulatory actions outside Thailand, e.g.,
o a restriction of the use of a medicinal product or its suspension
o strengthening or reviewing of the specific warnings/box warning

In general, the emerging safety issue is required to be reported to HPVC, the Thai FDA, as soon as MAHs
receives its first acknowledgement. The preliminary risk minimization measures should be provided, if
applicable.

7 Minimum criteria for reporting

All ICSRs should be completed as much as possible and aligned with the PDPA requirement before
submitting them to the NRA.
Four minimum criteria are required for ICSR validation:
(1) One Identifiable patient: Characterized by at least one of the following qualifying descriptors:
• initial, medical record number (from general practitioner, specialist, hospital, or investigation),
date of birth, age, age group, gestation period, or gender.
(2) One or more identifiable reporting sources: Characterized by the following parameters:
• Qualification, e.g., physician, pharmacist, other healthcare professional, consumer, other non-
healthcare professional
• name, initials
• address, e.g., reporter’s organization, email, or phone number

(3) At least one suspected substance/product: Interacting substances or medicinal products should also
be considered suspected.
(4) At least one adverse event/reaction: The report also does not qualify as a valid ICSR if it is reported
that the patient experienced a non-specified AE and there is no information on the type of AE.

It is recommended that as much information as possible be collected at the time of the initial report.
However, for the purpose of regulatory reporting, the minimum data elements for an ADR case are; an
identifiable reporter, an identifiable patient, an adverse reaction, and a suspect product. Lack of any of
these four elements means that the case is considered incomplete; however, MAHs are expected to
exercise due diligence to collect the missing data elements.

8 Data management
• Electronic data and paper reports of ICSR should be stored and treated with appropriate respect
for confidentiality regarding patients’ and reporters’ identifiability and in accordance with
applicable data protection laws.

56
• To ensure data security and confidentiality, strict control measures should be in place to provide
access to documents and databases only to authorized personnel. When data transfer occurs
within or between organizations, contractual agreements should be set up.
• Data storage should allow traceability (audit trail) of all data entered or modified, including dates
and sources of received data and dates and destinations of transmitted data.
• A procedure for the identification and management of duplicate cases at data entry and during
the generation of aggregated reports should be in place. Patient and reporter identifiability is
important to avoid case duplication, detect fraud, and facilitate follow-up of appropriate cases.
Assessing the patient and reporter’s identifiability, therefore, should be taken.

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 Chapter 6 Risk Management Plan (RMP)
A medicinal product is authorized based on its positive benefit-risk balance at that time for a specified
target population within its approved indication(s). However, not all adverse drug reactions (ADRs) and
risks will have been identified at the initial marketing authorization is granted.

It is generally recognized that safety information generated by clinical trials is relatively limited. The
benefit and risk of medicine used in routine clinical practice are frequently not studied before being
authorized. ADRs, which rarely occur or after a long time, may become apparent only once the product is
used in the real world. In addition, risk can result from medication errors, misuse, abuse, or off-label use.

To ensure that the benefit of the medicinal product remains outweighs the risk over time when it is used
in real-world settings. An appropriate risk management planning or strategy throughout the product’s life
cycle is needed. A set of pharmacovigilance activities and interventions should be designed to fully identify
and characterize the safety profile and appropriately manage the risks relating to medicinal products,
including the assessment of the effectiveness of those activities and interventions at the time of approval
time and post-marketing phase when new safety concerns are identified.

A risk management plan (RMP) is a document submitted as part of the dossier that is evaluated by
regulatory authorities before a medicinal product can be authorized and is regularly updated as new
information becomes available. The main aim of an RMP is to document the risk management system
considered necessary to identify, characterize, and minimize a medicinal product’s important risk.

The requirement of RMP has been put into practice across the world. However, the differences in local
regulation and the healthcare ecosystem within the country may lead to a different version of RMP. This
is due to a document of the RMP, especially the pharmacovigilance method and risk minimization
activities, which should be tailored to reflect such differences.

Definition
1) Identified risk An untoward occurrence for which there is adequate evidence of an association with
the medicinal product of interest. Examples include:
• an adverse reaction adequately demonstrated in non-clinical studies and confirmed by clinical
data
• an adverse reaction observed in well-designed clinical trials or epidemiological studies for
which the magnitude of the difference, compared with the comparator group on a parameter
of interest suggests a causal relationship
• an adverse reaction suggested by a number of well-documented spontaneous reports where
causality is strongly supported by temporal relationship and biological plausibility, such as
anaphylactic reactions or application site reactions
In a clinical trial, the comparator may be placebo, an active substance or non-exposure.

2. Potential risk An untoward occurrence for which there is some basis for suspicion of an association
with the medicinal product of interest but where this association has not been confirmed. Examples
include:
• non-clinical toxicological findings that have not been observed or resolved in clinical studies
• adverse events observed in clinical trials or epidemiological studies for which the magnitude
of the difference, compared with the comparator group (placebo or active substance, or

58
 unexposed group), on the parameter of interest raises a suspicion of, but is not large enough
to suggest, a causal relationship
• a signal arising from a spontaneous adverse reaction reporting system
• an event known to be associated with other active substances within the same class or which
could be expected to occur based on the properties of the medicinal product.

3. Missing information Gaps in knowledge about the safety of a medicinal product for certain
anticipated utilization (e.g., long-term use) or for use in particular patient populations, for which there
is insufficient knowledge to determine whether the safety profile differs from that characterized at
the time of submission of a particular RMP.
Examples of missing information include populations not studied (e.g. pregnant women or patients
with severe renal impairment) or where there is a high likelihood of off-label use. Nevertheless, the
absence of data itself (e.g., exclusion of a population from clinical studies) does not automatically
constitute a safety concern. Instead, the risk management planning should focus on situations that
might differ from the known safety profile. A scientific rationale is needed for the inclusion of that
population as missing information in the RMP.

4. Important identified risk and Important potential risk An identified risk or potential risk that could
have an impact on the risk-benefit balance of the product or have implications for public health. What
constitutes an important risk will depend upon several factors, including the impact on the individual,
the seriousness of the risk and the impact on public health. Normally, any risk that is likely to be
included in the contraindications or warnings and precautions section of the product information
should be considered important.

Principles of risk management

Risk management is a step-by-step process that involves evaluating the balance between the benefits and
risks of a product, implementing measures to minimize the risks while maintaining its benefits, assessing
the effectiveness of these measures, and adjusting them as needed.
Risk management's primary goal is to ensure that the benefits of a particular medicine outweigh its risks
to the maximum extent possible. It is essential to inform healthcare professionals and patients about the
potential risks and benefits of a specific treatment before making a decision. Regulators need to justify
their regulatory actions regarding patient safety and public health protection.

A risk management plan (RMP) is a widely recognized method to handle product safety. The purpose of
an RMP is to document the risk management system required to identify, analyze, and minimize the
significant risks of a medicinal product.

The Risk Management Plan (RMP) includes three important elements:

1. Identification or characterization of the safety profile of the medicinal product, with emphasis on
significant identified and potential risks, missing information, and safety concerns that require
proactive management or further study. (safety specification).
2. Planning pharmacovigilance activities to quantify clinically relevant risks and identify new adverse
reactions. (pharmacovigilance plan).
3. Planning and implementing risk minimization measures, including evaluating the effectiveness of
these activities. (risk minimization plan).

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RMP should be regularly reviewed and updated with new safety information. It should consider both
global and local needs, taking into account legal framework, genetic/ethnicity, environmental factors,
clinical practice guidelines, restrictions of use, and the regulator’s view on the benefit and harm balance.

New information about a medicine and external factors can alter its benefit-risk balance. Examples include
quality, safety, efficacy issues, introduction of new medicines or therapy, and discovery of problems with
existing therapy.
During the product's life cycle, it's crucial to consider the following questions for a critical review:
▪ What are the hazards associated with the product's properties, considering the manufacturing
and control processes?
▪ Which groups in the target population are more susceptible to the highest risks?
▪ Are the risks identified by independent scientific assessment predictable enough?
▪ Are there any uncertainties surrounding the assessment of risks?
▪ How can the risks be effectively mitigated?
▪ How effective are risk mitigation activities?

After reviewing, the list of safety concerns in the RMP may be reduced or the need for additional risk
minimization activities may change. Examples include:
▪ Important potential risks can be removed from the safety specification when accumulating
scientific and clinical data do not support the initial supposition, the impact to the individual
has been shown to be less than anticipated, resulting in the potential risk not being
considered important, or when there is no reasonable expectation that any PV activity can
further characterize the risk.
▪ Important potential risks need to be reclassified to “important identified risks” if scientific and
clinical data strengthen the association between the risk and the product.
▪ Important identified risks may be removed when the risk is fully characterized and
appropriately managed. For example; Products marketed for a long time for which there are
no outstanding additional PV activities and/or the risk minimization activities recommending
specific clinical measures have become fully integrated into standard clinical practice
▪ Missing information might not be appropriate anymore once new data become available or
when there is no reasonable expectation that the existing or future feasible PV activities could
further characterize the safety profile in the areas of missing information.
▪ Some risk minimization activities might need to be retained for the lifetime of the medicinal
product, e.g., pregnancy prevention programs. On the other hand, they may need to be
replaced with more effective activities in response to the findings of the effectiveness of risk
minimization evaluations.

Responsibilities for risk management

The MAHs and the NRA are directly involved in risk management. The RMP is drafted by the MAHs and
evaluated by the regulator.
The MAHs is responsible for having an appropriate risk management system in place and ensuring that
the knowledge and understanding of the product’s safety profile following its use in clinical practice are
critically reviewed. Include.
• Develop the RMP and update the RMP as new information emerges.
• Implement the activities and interventions outlined in the RMP
• Monitor PV data for changes in medicinal product risks and benefits, and report to NRA as needed.
• Collect and analyze information to monitor the effectiveness of these activities and interventions

60
• Actively update and promptly communicate when new safety information becomes available.

NRA has a key role in ensuring that RMPs serve as a tool to protect public health through the managed
implementation of risk minimization measures and Direct Health Profession Communications (DHPCs)
adapted according to the needs of local healthcare systems within the country. Discussions between NRAs
and MAHs at the early stages of drug development are recommended for the development of the RMP
and any additional PV activities and risk minimization measures.

Objectives of RMP
The main aim of RMP is to optimize a medicinal product’s benefit/risk balance for the individual patient
and the target population. The objectives of an RMP are to;
• Identify or characterize the safety profile of the medicinal product(s) concerned
• Indicate how to characterize further the safety profile of the medicinal product(s) concerned
• Document measures to prevent or minimize the risks associated with the medicinal product, including
an assessment of the effectiveness of those interventions
• Document post-authorization obligations that have been imposed as a condition of the marketing
authorization

Content of the RMP

The RMP consists of 7 parts with three key components, including safety specification, pharmacovigilance
plan, and risk minimization plan.

An overview of the parts and modules of the RMP:

Part I Product(s) overview
Part II Safety specification
Module SI Epidemiology of the indication(s) and target population(s)
Module SII Non-clinical part of the safety specification
Module SIII Clinical trial exposure
Module SIV Populations not studied in clinical trials
Module SV Post-authorization experience
Module SVI Identified and potential risk
Module SVII Summary of the safety concerns
Part III Pharmacovigilance plan (including post-authorization safety studies)
Part IV Plans for post-authorization efficacy studies
Part V Risk minimization measures (including evaluation of the effectiveness of risk minimization
activities)
Part VI Summary of the risk management plan
Part VII Annexes

Part I Product(s) overview

The administrative information on the RMP and an overview of the product(s) should include :
• active substance(s) (INN name or common name);
• pharmacotherapeutic group(s) (ATC code);
• name of MAHs or applicant;
• trade name(s);
• brief description of the product including:

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 - chemical class;
- mode of action;
- its composition (origin of active substance of biologicals, adjuvants or residues for vaccines);
• indication: approved and proposed (if any);
• dosage (summary information – only related to main population)
• pharmaceutical forms and strengths;
• date and country of first authorization worldwide (if applicable);
• date and country of first launch worldwide (if applicable);
• number of medicinal product(s) to which this RMP refers.
Part II Safety specification
The safety specification summarizes the safety profile of the medicinal product including identified risks,
potential risks, and missing information. It highlights key safety concerns that need proactive
management or further study.
Include information on at-risk populations and safety concerns that require further investigation post-
authorization. The level of detail should correspond to identified and potential risks and the product's life
cycle stage.

This safety specification helps MAHs and regulators identify data needs and develop PV and risk
minimization plans. It's divided into 8 modules.
Module SI - Epidemiology of the Indication(s) and Target Population(s)

• incidence, prevalence, and mortality of the target disease

• demographics of the population in the authorized /proposed indication
• risk factors for the disease
• the main existing treatment options
• natural history of the indicated condition in the untreated population, including mortality and
morbidity
• important co-morbidities in the target population

The following general points should be considered for the assessor;

• How will the medicinal product be used?
• Who will use medicinal products?
• How serious is the condition?
• What option do they have?
• What put them at risk of safety concerns?
• What other conditions are they likely to have?
• What other medicines are they likely to be taken?

Module SII - Non-clinical part of the safety

This RMP module should present a high-level summary of the significant non-clinical safety findings, for
example:
• toxicity (acute or repeat-dose toxicity, reproductive/developmental toxicity, nephrotoxicity,
hepatotoxicity, genotoxicity, carcinogenicity);
• safety pharmacology (cardiovascular system, including QT prolongation, nervous system);
• drug interaction

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 • other toxicity such as quality aspects, if relevant to safety (genotoxic impurities)
If the product is intended for use in special populations, consideration should be given to whether specific
nonclinical data needs exist.
Check and explain why findings are relevant to human use. Regularly assess the relevance of this section.
Remove non-clinical safety concerns if no longer relevant or not confirmed by post-marketing experience.

The following general point should be considered for assessor.

• Do the non-clinical findings raise any concerns for the safety in humans?
• Do any of the non-clinical findings require further investigation?

Module SIII - clinical part of the safety

To evaluate the limitations of the human safety database, clinical trial data should be provided in tables
or graphs. This data should include the number of patients and patient time exposed to the medication.
Pooled data is preferred over individual trial data, unless there are specific reasons not to. Stratify clinical
trial exposure summary based on relevant parameters and by trial type. Stratifications would normally
include;
• Age group and gender
• Duration of exposure
• Dose
• Ethnic origin
For the RMP with multiple medicinal products, provide a population table for each product and a
combined table where appropriate. Patients enrolled in multiple trials should only be counted once in the
demographic tables, and discrepancies between tables must be explained.

The following general points should be considered for the assessor.

• Which population is usually under-represented in clinical trials?
• Which risk is clinically significant in these groups?

Module SIV - Populations not studied in clinical trials

This module discusses populations that are understudied or only limitedly studied during the pre-approval
phase. It also highlights the limitations of the clinical trial population in predicting the safety of the
medicinal product(s) in real-life use.

Exclusion criteria should only be mentioned if relevant to the approved and proposed indication, and if
the use in such populations might be associated with risks. Evidence of product use in excluded
populations being associated with an undesirable clinical outcome should be included as a potential risk.

Information on low exposure of special populations or lack thereof, such as pregnant and breastfeeding
women, patients with renal, hepatic, or cardiac impairment, populations with genetic polymorphisms,
immune-compromised patients, and patients of different ethnic origins, should be described
appropriately.
The following general points should be considered for the assessor.
• Which populations were not studied in clinical trials?
• Who was excluded from clinical trials?
• Will these groups use the medicine (within its indication) when the product is marketed?

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 • What are the implications of these gaps for post-market safety?
• Which area of missing information should be included in the summary of concern?

Module SV - Post-authorization experience

This module summarizes post-marketing data from authorized regions and medicinal products containing
the same active substance. Its purpose is to provide an overview of the product's exposure in the post-
authorization phase for risk management planning, and to discuss the product's on- and off-label use in
special populations when relevant for risk identification in module SVI.

The following general points should be considered by the assessor;

• How much experience is there with the product?
• Have problems arisen in real-world use?

Module SVI - Identified, potential and missing risks

This module should discuss the identification of important identified and important potential risks, and
missing information. The following safety topics should be discussed if they lead to risks of the product:
• overdose, whether intentional or accidental.
• medication errors;
• infectious transmission due to the manufacturing process or the materials involved;
• off-label use;
• pharmacological class effects;
• pharmacokinetics and pharmacodynamics interactions;
• pregnant and lactating women;
• effect on fertility;
• administration procedure;
• disposal of the used product;
• pediatric safety issues.

SVI.1 “Identification of safety concerns in the initial RMP submission”

This section is only for initial marketing authorization applications and should not change after
approval. Risks are categorized based on evidence of causal association with the product. Sources of
adverse reaction risks include non-clinical data, clinical trials, epidemiological studies, spontaneous
reports, and published literature.

SVI.2 “Risks considered important for inclusion in the list of safety concerns” and “Risks not
considered important for inclusion in the list of safety concerns”
The RMP should only include confirmed risks that impact on the risk-benefit balance. Not all adverse
reactions are considered risks, and not all risks are important enough for the safety concerns list. Non-
included risks' seriousness, frequency, and benefit-risk impact should be discussed. If not included,
adherence to clinical practice may be explained.

SVI.3 “New safety concerns and reclassification with a submission of an updated RMP”
This section applies to RMP updates after marketing authorization. Provide justification for
reclassification or removal of identified/potential risk with reference to safety data, e.g. changes in
scientific evidence or previous regulatory requests.

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 SVI.4 “Details of important identified risks, important potential risks, and missing information”
This section covers all stages of a product's life cycle. Provide data from all possible sources, such as
clinical trials, literature, post-marketing data, etc. Important risks depend on factors such as the
likelihood to impact the benefit-risk balance, frequency, severity, and seriousness of the outcome,
and the context of the condition. If a risk has minimal clinical impact, is unlikely to occur, or is well-
known and managed, it is not considered significant.

For identified significant risks, describe evidence supporting the causal relationship, severity,
seriousness, frequency, reversibility, and at-risk groups. Discuss risk factors and potential
mechanisms.
Present evidence that led to the conclusion of an important potential risk. For significant potential
risks, evaluate further to understand the association and review incidence rates.

Include any clinically significant risks likely to be in the Contraindications or Warnings and Precautions
section of the package insert or Company Core Data Sheet (CCDS).
In RMPs with multiple products, specify safety concerns for each product, especially for fixed dose
combination products.

Presentation of important identified risks and important potential risks

• name of important identified/potential risk (MedDRA terms when appropriate);
• potential mechanisms (biological mechanisms);
• evidence source(s) and strength of evidence (the scientific basis for suspecting the association);
• characterization of the risk: frequency, absolute risk, relative risk, severity, reversibility, long-term
outcomes, and impact on quality of life;
• risk factors and risk groups, including patient factors, dose-related, at-risk period, additive or
synergistic factors
• Preventability involves predicting and minimizing the risk of ADRs while detecting them early to
reduce their severity.
• Impact on the risk-benefit balance of the product, including the actual impact and the expected
impact
• Public health impact, consider absolute risk and overall outcome at the population level

Presentation of the missing information

• name of the missing information (using MedDRA terms when appropriate or population name);
• evidence source that the safety profile is expected to be different than in the general target
population;
• population in need of further characterization, or risk anticipated in the population of not
studied/consequence of the missing information, as appropriate.

Module SVII - Summary of the safety concerns

List safety concerns with categories at the end of the safety specification, summarizing previous
Module SVI issues.
• Important identified risks
• Important potential risks

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 • Missing information
Summarize each product in RMP if safety concerns vary. Summary of minimum RMP requirements for
initial marketing authorization applications

Part III: Pharmacovigilance Plan (including post-authorization safety studies)

The pharmacovigilance plan outlines how the MAHs will identify and quantify safety concerns in the safety
specification:
• identify new safety concerns.
• further characterize safety concerns (severity, frequency, and risk factors);
• investigate whether a potential risk is confirmed as an identified risk or refuted;
• explore the missing information.
• measure the effectiveness of risk minimization activities.

When creating a PV plan, prioritize safety concerns in RMP module SVII. The plan should match the
product's benefits and risks. MAHs usually create it and should discuss it with NRA during product
development.
Pharmacovigilance activities can be routine or additional. For products with potential risks or missing
information, additional actions should be taken.

Routine pharmacovigilance activities

Routine pharmacovigilance is the minimum set of activities required for all medicinal products. Activities
might include safety evaluation incorporated into clinical trials, and the monitoring and reporting of
adverse events. The routine pharmacovigilance should include the following activities:
• have a system and process to collect and report all suspected ADRs to responsible staff
• Prepare and submit individual case safety reports (ICSRs) and periodic benefit risk evaluation
reports (PBRERs), if applicable, within the regulatory timeline
• Monitor product safety, evaluate issues, update labeling, and liaise with regulators.
• Monitor and report new safety concerns and measures taken by a stringent regulatory authority
(SRA).
• Other national regulatory requirements (specific AE)

Additional pharmacovigilance activities

MAHs should propose non-routine pharmacovigilance activities to explore the potential risk or missing
information. Studies may be non-clinical, clinical, or non-interventional. The activities should relate to
safety concerns in the safety specification. Example;
• Long-term follow-up extensions of ongoing clinical trial(s)
• Cohort studies including cohort event monitoring studies or prospective registry studies
• Further effort is to evaluate the missing data
• Early phase post marketing vigilance (EPPV)

The medicinal products with high risk, include products with only early phase of clinical studies, should
propose additional Pharmacovigilance plan.

If in doubt about the need for additional pharmacovigilance, consult NRAs. Refer to the post-authorization
safety study (PASS) chapter for guidance on study protocol preparation and conducting the study.

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A table summary of all ongoing and planned additional pharmacovigilance should be presented
• study name and status
• objectives
• rationale or list of safety concerns
• monitoring for safety issues and proposed action(s)
• milestones for evaluation and reporting

Regulatory authorities may request study protocols for evaluation. Approved protocols for studies in the
pharmacovigilance plan should be included in the RMP, and removed once the study reports are
submitted.

Part IV: Plans for Post-Authorization Efficacy Studies

List planned and ongoing post-authorization efficacy studies (PAES) imposed as a condition of marketing
authorization. If no studies are required, leave it empty.

Part V: Risk Minimization Measures

(including evaluation of the effectiveness of activities).
This part should outline specific measures for minimizing risks associated with individual safety concerns.
Risk minimization measures (RMMs) aim to prevent adverse reactions associated with medication
exposure and improve patient outcomes. This includes activities to prevent medication errors.
Select RMMs based on safety concern characteristics outlined in the safety specification. Evaluate each
concern individually and choose tools accordingly;
• Inherent in identifying or potential risk (frequency, seriousness, severity) and preventability
• targeted population
• intended and possible use
• healthcare setting for the use (in patient vs. self-administration).

One measure can address multiple safety concerns and vice versa. Local conditions and adaptations must
be considered. Risk minimization activities may not be feasible in different regions due to varying
healthcare systems, geography, and populations.

A risk immunization plan consists of routine risk minimization activities and additional risk minimization
activities. All activities should have a clearly identifiable objective.

1. Routine risk minimization activities (measures)

For all medicinal products, risk minimization is generally addressed by routine risk minimization
activities. These include;
o Summary of product characteristics (SmPC)
o Package leaflet (PL),
o Patient information leaflet (PIL)
o Product labeling (outer packaging)
o Legal status of the product
o Pack size & design, product design
o Instruction for use document
o Stability and cold chain management

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 2. Additional risk minimization activities (measures)
Focus on important safety concerns that routine measures can't manage. If additional risk
minimization activities are needed, detail their objectives, justification, and effectiveness
measurement. Keep these activities separate from promotional activities.

In determining the need for additional risk minimization activities and their effectiveness, MAHs
and regulatory authorities should evaluate:
o Consider population, frequency, severity, context, impact, and preventability when
developing additional RMMs
o Healthcare professionals should be advised on appropriate patient selection, excluding
contraindicated patients. Proper monitoring during treatment is essential to detect and
manage early adverse reactions
o The effectiveness of such activities should be weighed against the burden they may
impose on the system and their potential unintended effects
o The healthcare professionals and patients should be guided to follow specific behaviors
for each step of the treatment process
o The tools should be proportionate to the risk, effective, timely, and not overly
burdensome for patients or the healthcare system.
o MAHs must review and assess risk minimization measures regularly and notify regulatory
authorities of any subsequent changes before implementation.

Additional risk minimization activities may include:

1) Educational programs.
a) Patient education materials (printed materials, website, alert cards)
• Targeting a specific patient group
• Provide information on the proper use of products
• Enhance awareness of the early signs and symptoms of ADRs
• Remind the patient of a certain action to take for risk minimization
b) Professional education/materials, including prescribing / dispensing guide, targeted
education
• Selection of patients
• treatment management (dosage, test, and monitor)
• Special administration procedures
• Information needs to be given to patient
• Direct healthcare professional communications (DHPCs)

2) Controlled access program

This is to regulate access to medicines beyond routine control measures. Programs must be
adapted to local healthcare settings in collaboration with regulatory authorities. Examples:
• Controlled prescription and supply system
• Prescriber/dispenser certification program
• Forms for patient information exchange between prescriber and dispenser
• Wholesaler / Pharmacy registration
• Testing before use
• Patient monitor program (patient registry)
3) Pregnancy prevention program

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 Actions to reduce pregnancy exposure during treatment with potentially teratogenic effects.
• To avoid pregnancy during the treatment course.
o educational material
o pregnancy test before prescription
• Restriction of the medication amount in a single prescription
• Counselling for desired, unplanned, or adverse pregnancy outcome

When updating the RMP, discuss the impact of additional risk minimization activities. Include the results
of any formal assessment(s) of risk minimization activities. Consider alternative activities if a strategy is
ineffective or burdensome. Comment on whether additional or different risk minimization activities are
needed or if current measures can be removed.
Effectiveness evaluation of risk minimization activities
MAHs need to monitor the effectiveness of RMMs, including routine and additional RMM. Evaluation can
focus on significant patient and public health RMM, measurement details, or intended/unintended
outcomes. MAHs and NRAs must agree on success indicators for the evaluation plan.
Quantitative evaluations of RMM effectiveness (prescription patterns and health outcomes) are crucial
for decision-making. Qualitative research (observed changes or lack of intended changes in knowledge or
behaviors) can help understand the reasons for the success/failure of regulatory actions and define
objectives for quantitative analysis. Its findings can help consider corrective actions.
Summary of Risk Minimization Measures
A table that lists routine and additional risk minimization activities organized by safety concerns should
be included in this section.

Part VI: Summary of the RMP

This summary should be consistent with the information presented in other RMP parts. It should contain
the following information:
• the medicinal product;
• summary of safety concerns and missing information;
• routine and additional risk minimization measures;
• additional pharmacovigilance activities.

Update summary for important RMP changes. The important changes include.
• new important identified or potential risks, change or removal of a safety concern;
• inclusion or removal of additional RMMs or recommendation of any clinical measures to address
the risk
• major changes to the PV plan (new studies).

Transparency of RMP

The NRAs should make publicly available a summary of RMP and activities, product information and
conditions to marketing authorization on regulatory website. This is to ensure that all relevant
stakeholders who are involved in these products are aware of all RMP-related commitment activities,
and their product conditions.

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 Requirements of RMP in Thailand

According to the Thai FDA guidance for new application and re-exam of the marketing authorization
license in 2023, RMP is currently required for medicinal products used by humans.

Whereas, both medicinal products used by animals and traditional products for animal use have required
RMP during re-exam of license only.

In 2023 Thailand, the Safety Monitoring Program (SMP) is no longer applicable for medicinal products, but
RMP is currently an essential tool to monitor and manage the benefit-risk and safety concerns instead.

1. In the post-authorization phase, an RMP update or a new RMP may need to be submitted at any
time:
1. The NRA should request RMP when there is a risk concern that affects the risk-benefit balance
2. Any significant change to an existing marketing authorization:
a. Data changes may require updates to safety concerns, PV activities, or risk minimization plans
b. Biologic products need significant changes in indication, dosage, route of administration, or
manufacturing process.
▪ The need for RMP or an update to the RMP should be discussed with the NRA before submitting

2. RMPs with new applications

▪ Full initial marketing authorization applications require all parts of the RMP, while other
applications need a proportionate RMP with reduced content requirements. Table 2 proposes a
summary of RMP modules/parts requirements based on risk proportionality principle for different
product categories.

▪ The submitted RMP should follow the structure and templates provided in the regulatory
guidelines. In case MAHs plans to submit Eu-RMP or core/global RMP, a Thailand-specific annex
needs to be included, except RMP is developed specifically for Thailand. However, core RMP must
include the modules of the EU RMP.

Thailand-specific annex (TSA) should provide information that is important in assessing:

a) The risk in Thailand and the appropriateness of the proposed plan and activities. Whether
there is any safety concern that may be unique to Thailand.
b) Health system differences and how activities will be adapted to the local context.
c) The relevance of the international PV plan and risk minimization activities to Thailand and
reasons for any differences from activities planned overseas.
d) Data lock point of the current RMP (less than 6 months before the RMP sign-off date)
e) Sign-off date and the version number of the RMP

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 Thailand-specific annex (TSA) should address the following points:
a) any differences in safety concerns between the submitted RMP (EU or core RMP) and
Thailand and ensure that these are taken into account in determining an adequate risk
management system;
b) any risk minimization activities not reflected in the submitted RMP that are required to
adequately address the safety concerns in Thailand. (such as differences between the EU
SmPC and Thailand PI in the wording of precautions or contraindications or additional PV
activities required by the Thai FDA);
c) details of the dissemination and evaluation of the effectiveness of risk minimization
activities in Thailand;
d) milestones and timelines for reporting on additional PV and risk minimization activities to
the Thai FDA.

The Thailand-specific annex (TSA) should include the following parts (as minimum):

1. Product overview in Thailand

2. Safety specification
a. Thailand-specific safety concerns.
b. Proposed changes to Thailand-specific safety concerns, including reasons for the
reclassification or removal from the list of safety concerns.
3. Pharmacovigilance plan
a. Local routine PV activities (summary or list of routine PV activities)
b. Local additional pharmacovigilance activities (summary table of additional PV activities)
4. Risk minimization plan
a. Routine risk minimization activities ( describe the routine activities for each safety concern)
b. Additional risk minimization activities (describe specific activities to be undertaken in
Thailand)
5. Additional Information (if applicable)

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 Table 2 RMP component of the product groups in Thailand

Product Part I Part II Part Part Part Part

III IV V VI
SI SII SIII SIV SV SVI SVII SVIII

1. Full MA application (New chemical entity, Biologics include √ √ √ √ √ √ √ √ √ √ √ √ √

biosimilar, ATMPs, conditional for emergency use)
2.a. Fixed combination product – new active substance √ ₸ ₸ ₸ ₸ ₸ ₸ √ √ √ √ √ √

2.b. Fixed combination product – no new active substance √ † † ‡ √ √ * ∫ √

3/. Hybrid product1 √ † † † √ √ √ ∫ √

4. Generic product √ ‡ √ √ * ∫ √

5. Well-established medicinal use product √ √ √ √ √ √ √

1Hybrid medicine = authorized medicine contain the same active substance, but where there are certain differences
between the two medicines such as in their strength, indication or pharmaceutical form
√ = applicable/relevant
‡ = relevant only if “originator” product does not have an RMP
* = relevant only when a PAES was imposed for the “originator” product
∫ = statement of alignment of safety information in PI is sufficient
† = requirements based on risk proportionality principle, addressing new data generated or differences
with the “originator” product
₸ = focus on the new active substance

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 Chapter 7 Safety communication

Marketing authorization holders (MAHs) and National regulatory authorities (NRAs) have a public health
responsibility to communicate safety information for effective pharmacovigilance, promoting rational,
safe medicine use, preventing harm from adverse reactions, minimizing risks, and protecting patients and
public health.
Safety communication contains various types of information on medicines, such as statutory information
found in product information and public assessment reports.
This chapter’s aim is to guide any organizations that involve PV functions and need to prepare the
communication of important new safety information for their medicinal products. This refers to new
information about a previously known or unknown risk of a medicine that could have an impact on a
medicine's risk-benefit balance and the way it should be used. Therefore, the term "safety
communication" in this chapter should be understood as referring to new safety information.

Objectives of safety communication

▪ Provide timely, evidence-based information on the safe and effective use of medicines.
▪ facilitate changes to healthcare practices (including self-medication practices) where necessary.
▪ change attitudes, decisions and behaviors related the use of medicines;
▪ support risk minimization behavior;
▪ facilitate informed decisions on the rational use of medicines.

Principles of safety communication

▪ Safety communication should deliver clear, accurate, and consistent messages to reach the right
audiences at the right time for them to take appropriate action.
▪ Appropriate language should be used to tailor the information to the target audience whilst
maintaining accuracy and consistency.
▪ The need for communicating safety information should be considered throughout the risk
management process. Adequate coordination and cooperation should occur between parties
issuing safety communications.
▪ At a later stage, relevant safety communication should be provided in follow-up communication,
such as updates on the resolution of safety concerns and recommendations. In addition, the
effectiveness of safety communication should be evaluated where appropriate and possible.
Target audiences
▪ Primary target audiences for safety communications related to medicinal products are patients,
carers, and healthcare professionals who handle, prescribe, dispense, administer, or take them.
▪ Healthcare professionals are the primary audience for ensuring the safe and effective use of
medicines. Effective safety communication equips them with the necessary information to take
appropriate measures to mitigate risks and provide their patients with clear and useful
information.

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 ▪ Multipliers such as patient, consumer, and healthcare professional organizations can disseminate
vital safety information to target audiences.
▪ The media's role in sharing medicine information is crucial. Safety information should come
directly from trustworthy sources to ensure accuracy and unbiased reporting. The public needs
reliable information to make informed decisions about their health.

Content of safety communication

Safety communication must be presented objectively and not contain misleading information.
Content should contain the following messages.
▪ Important new information on the product impacting risk-benefit balance under all conditions of
use.
▪ Clearly state the reason for initiating any safety communication.
▪ Ensure completeness by considering risks, harm, benefits, alternatives, and acknowledging
knowledge uncertainty.
▪ Guidelines for managing safety concerns of products, including risks of not treating, when
necessary, for HCPs and patients
▪ NRAs and MAHs agree on safety information when applicable.
▪ Details regarding any proposed changes to the product information are provided.
▪ The content should be customized to meet the specific requirements of the intended audience.
▪ List relevant literature references and any necessary background information.
▪ Ask to report all suspected adverse reactions to Health Products Vigilance Center (HPVC) , Thai
FDA.

Types of safety communication

Consider the tools and channels for safety communication to meet growing audience
expectations. These have become numerous and varied over time. Common uses include
providing product information.

A. Direct healthcare professional communication (DHPC)

DHPC is a direct communication intervention where the MAHs or NRAs deliver crucial safety
information directly to healthcare professionals. It informs them of the need to take specific
actions or modify their practices concerning a medicinal product.
MAHs and NRAs must agree on DHPC content and communication plan before issuance. Details
include recipients, timetable, and channels for DHPC dissemination.
• Complement by other communication tools and channels.
• Cover an additional risk minimization measure.
• Disseminate when there is a need to take immediate action or change current practice
due to safety concerns.
o Example: suspension, withdrawal or revocation of a marketing authorization, a
restriction in availability, discontinuation of products with potential harmful
effects on patient care, or new major warnings or precautions.

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 A DHPC may be disseminated by a regulatory authority or requested to be disseminated by the
MAHs in any situation deemed necessary for the safe and effective use of a medicinal product.

B. Communication materials by National Regulatory Authority (NRA)

The NRA can directly communicate safety-related information to specific groups such as
healthcare providers, patients, journalists, and the public. These communications are typically
posted on the regulatory authority's website and are usually issued along with other means of
communicating safety concerns, such as a DHPC.
It is essential to consider the target audience and tailor both the language and structure
accordingly. The content should include recommendations and advice from regulatory authorities
on how to minimize risks for each target group, as well as relevant background information.
Additionally, it may be helpful to include links to further information.
For effective dissemination and accessibility, it is important to use appropriate tools and channels.
For instance, the NRA can send a press release directly to journalists while also publishing it on
their website. If a DHPC and/or communication from the NRA is prepared, it is ideal for healthcare
professionals to receive it prior to or around the same time as the publication or distribution of
the press release, so that they can be better prepared to respond to patients.

C. Bulletin and newsletters

Bulletins and newsletters are effective means of providing regular information about medicines,
their safety, and effectiveness. These tools can serve as reminders of previous communications
and can reach a large audience through web-based and other available means.
D. Online safety communication
In the current digital age, online safety communication can be effectively communicated through
social media and other web tools. However, when using newer and faster communication
channels, it is important to ensure that the accuracy of the information released is not
compromised. Communication practices should consider the various digital communication tools
that are emerging and being used by different target audiences.
E. Responding to inquiries from the public
NRAs and MAHs should establish a system to respond to public inquiries about medicines. The
response should consider the information available to the public and include relevant
recommendations and advice to patients and healthcare providers issued by the regulatory
authority. If the query is related to individual treatment advice, patients should be advised to
consult a healthcare professional.
Effectiveness of safety communication
• Effective safety communication is achieved when the intended message is received and
understood by the target audience, resulting in appropriate action being taken.
• It is recommended to evaluate and measure the effectiveness of safety communication using
appropriate mechanisms. A research-based approach can be used to establish the effectiveness

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 of safety communication, which may measure different outcomes such as behavior, attitudes, and
knowledge. The evaluation can also include factors other than the performance of the tools.
• In the case of DHPCs, it is important for MAHs to inform regulatory authorities about the number
of HCPs who received the DHPC and the problems detected during dissemination. Appropriate
action should be taken to correct the situation or prevent similar problems in the future.

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 Chapter 8 Periodic Benefit-Risk Evaluation Report (PBRER)

This chapter is intended to explain the format and content of the Periodic Benefit-Risk Evaluation Report
(PBRER) for marketed products.

Upon approval, new medicinal products demonstrate safety and efficacy through a limited patient pool,
often excluding higher-risk groups from clinical trials. Long-term treatment data are constrained, and
monitoring in trials is more intensive. In clinical practice, a broader patient range is treated, and rare
events may occur. Continuous analysis of safety, efficacy, and effectiveness is crucial for prompt responses
to important findings. Periodic assessments are needed for an overall understanding. While new
information is predominantly safety-related, details about effectiveness, limitations, and alternatives
contribute to the ongoing benefit-risk assessment.

The ICH Guideline E2C, Clinical Safety Data Management, was finalized in 1996 and updated in 2012. It is
regarded as a standardized periodic safety report and is used as a reference for developing the Thai
version of PBRER.

Objectives
The principal aim of a PBRER is to provide an updated, comprehensive, and critical analysis of new or
emerging information concerning the risks and benefits of the medicinal product in approved indications.
This allows for an assessment of the overall benefit-risk profile. The report should evaluate new
information obtained by the Marketing Authorization Holders (MAHs) during the reporting interval. This
includes:
- summarizing relevant safety and efficacy data
- assessing consistency with the known benefit and risk profile
- conducting an integrated benefit-risk evaluation for approved indications
- proposing actions for optimizing the benefit-risk profile when appropriate
The PBRER is not intended for initial notification of significant new safety information or for detecting new
safety concerns; urgent safety information should be reported through the appropriate mechanism.

Scope of the PBRER

The PBRER integrates the product's overall knowledge, balancing it with new information. The primary
emphasis of the PBRER is the assessment of significant new safety information in the context of relevant
efficacy/effectiveness information since the international birth date (IBD) or the development
international birth date (DIBD). This entails a comprehensive safety assessment as well as an integrated
benefit-risk evaluation of both historical and recent data. All relevant new safety and
efficacy/effectiveness information identified during the reporting interval should be addressed in the
appropriate sections of the PBRER.

Possible sources of information that may be used in the preparation of the PBRER are illustrated in
Appendix E of the ICH-E2C (R2). Examples of included information sources, but are not limited to, are
• 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 (for additional information see ICH E2D Guideline, Post-approval Safety
Data Management: Definitions and Standards for Expedited Reporting)
• observational studies such as registries

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 • product usage data and drug utilization information
• published scientific literature or reports from abstracts including information presented at
scientific meetings
• unpublished manuscripts
• active surveillance systems (for example, sentinel sites);
• systematic reviews and meta-analyses
• information arising from licensing partners, other sponsors or academic institutions/research
networks
• patient support programs
• investigations of product quality
• information from regulatory authorities

Given that drug development frequently continues after approval, any relevant insights from post-
marketing studies or clinical trials in unapproved indications or populations should be included in the
PBRER. Similarly, understanding the safety of a medicinal product from uses beyond the approved
indication(s) will be considered for the risk evaluation, when applicable and suitable.

PBRER in Thailand
Currently, PBRER is required to submit upon Thai FDA request only. All MAHs that own new drugs,
biologics, hybrid products, combination products, and biosimilars, on the other hand, should develop
PBRER to evaluate and update the benefit-risk profile on a regular basis.

PBRER and other documents

There are many types of periodic reports required during the post-approval period to assist in the planning
of pharmacovigilance activities, including:
• PSUR (ICH guideline E2C(R1))
• DSUR (ICH guideline E2F)
• Safety specification (ICH guideline E2E)

These documents are standalone by nature, with distinct regulatory purposes and periodicities, and are
reviewed by different divisions. MAHs should be cautious when using these documents, as there may be
overlaps or inconsistencies.

Modular approach
The PBRER should be developed in such a way that the content of several sections may be used for
sections of other documents as a basis for a modular approach. This will facilitate the responsible person
in simultaneously editing all documents at once, promote consistency across various documents (PBRER,
DSUR, safety specification), avoid duplication, and update product information.

General principles

1. Single PBRER for an active substance

The PBRER should provide information on all approved indications, dosage forms, and regimens
for the product, with a single Data Lock Point (DLP).
In some circumstances,
• It will be appropriate to present data by indication, dosage form, dosing regimen, or
population (e.g. children vs. adults) within the relevant section(s) of the PBRER.

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 • It will be appropriate to submit separate PBRERs when an active ingredient used in two
formulations for the different routes of administration (e.g., oral and topical) are for
entirely different indications. In this situation, the MAHs should preferably notify the DRA
at the time of approval.

2. PBRER for fixed-dose combination products

For combinations of substances, information may be reported either in a separate PBRER or
included as separate presentations in the report for one of the individual substances, depending
on the circumstances. Listing related PBRERs is considered important.

3. Products manufactured and/or marketed by more than one company

Each MAHs should prepare PBRERs for its own product. In contractual relationships,
responsibilities for PBRER preparation and submission should be specified in writing.
When data from a partner company might contribute meaningfully to the benefit-risk analyses
and influence the reporting company’s product information, these data should be included and
discussed in the PBRER.

4. Reference information
PBRER aims to provide updated benefit-risk evaluation information to ensure appropriate and
safe use of the medical product. The reference information, both the indication and risk, should
be gathered from all countries where the products were marketing authorized. The reference
product information could be retrieved from:
• Company Core Data Sheet (CCDS)
• Other options for reference product information such as package insert or summary of
product characteristics

Significant changes to the reference product information/reference safety information (RSI) made
during the interval should be described in Section 4 of the PBRER (“Changes to Reference Safety
Information”) and include:
o changes to contraindications, warnings/precautions sections of the RSI
o addition of ADR(s) and interactions
o addition of important new information on use in overdose; and
o removal of an indication or other restrictions for safety or lack of efficacy reasons.
Significant changes to the RSI made after the Data Lock Point (DLP) but before submission of the
PBRER should be included in Section 14 of the report (Late Breaking Information), if feasible.

5. Level of detail within PBRER

The level of detail in PBRER sections should align with the known or emerging benefits and risks
of the medicinal product.
In the presence of significant new safety data, a detailed presentation along with relevant benefit
information for a robust benefit-risk analysis should be described. Conversely, if there is minimal
new safety information during the reporting period, a concise summary of baseline benefit
information is adequate, and the benefit-risk evaluation will primarily focus on updated safety
data for the interval.
The sections that evaluate safety data, efficacy/effectiveness data, safety signals, and benefit-risk
will vary among individual reports.

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6. Efficacy/Effectiveness
The terms 'efficacy/effectiveness' are utilized to clarify that information from both clinical trials
and routine medical practice can be included in the PBRER.

7. Benefit-risk evaluation
Benefit-risk information must be evaluated throughout the product life cycle. Benefit-risk
evaluation is a crucial criterion for product market authorization. Once the product is approved
and widely used, ongoing benefit-risk assessment is essential to ensure that benefits continue to
outweigh risks and to guarantee consumer safety.

8. Periodicity and PBRER data lock point

A. International Birth Date (IBD) and Data Lock Point (DLP)

IBD is the date of the first marketing approval for any product containing the active substance
granted to any company in any country in the world.

The DLP is the date designated as the cut-off for data to be included in a PBRER. Approvals of
products containing the same active ingredient but with different dosage forms, formulations, or
uses (indications, routes, and/or populations) will have the same IBD but may have different DLP.

When a separate PBRER is prepared for a fixed-dose combination product, the DLP for that PBRER
can be based on either the earliest IBD of one of the component active substances or the IBD of
the first marketing approval anywhere in the world for the fixed-dose combination.

When clinical development of a medicinal product continues following marketing approval, if

desired by the sponsor/MAH, the beginning of the DSUR reporting interval can be synchronized
with the IBD-based cycle, so that both the DSUR and PBRER can be prepared at the same time,
using the same DLP. This approach will facilitate the use of the proposed common
sections/modules for both the PBRER and DSUR when both are submitted annually

B. Managing difference frequencies of PBRER submission

Submission of a PBRER depends on factors such as approval dates, the length of time the product
has been on the market, and the extent of new benefit-risk information of the product.

The PBRER is intended to be submitted with more frequency when the product is new to the
market and less frequency when both benefit and risk information become more available.

ICH-E6 (R2) and many countries usually require the MAHs to submit PBRER every 6 months in the
first 2 years after the product is marketing authorized.

An ad hoc PBRER may be requested by the NRA which is a completely new report prepared by
the MAH. It should be stand-alone and should reflect new and cumulative information currently
available to the MAHs.

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 Sections that provide interval information are likely to be updated for each PBRER, and the
content used in the previous PBRER can be reviewed and reused for sections where no new
information has arisen since the preparation of the last PBRER, if appropriate. It may be
determined that sections providing an evaluation of cumulative data may not need to be updated
if the content remains up to date with current information.

MAHs may be required to submit PBRER according to the following schedule.

• First 2 years: PBRER submission every 6 months
• Year 3rd-5th: PBRER submission every year

The first PBRER submitted should have DLP no later than six months after marketing
authorization approval.

For hybrid products, the latest PBRER is expected to be submitted once in the following
circumstances: new indication, new chemical form, new dosage form, new dosage strength, and
new route of administration.

In any case, the PBRER could not be submitted according to the PBRER submission requirement,
the NRAs should be notified, and their agreement obtained for a new schedule of PBRER
submission.

C. Time interval between data lock point and the submission

As a result of the expanded scope of the PBRER, the time interval between the DLP and the
submission of PBRERs should be as follows:
• PBRERs covering intervals of 6 or 12 months: within 70 calendar days
• PBRERs covering intervals in excess of 12 months: within 90 calendar days
• ad hoc PBRERs: 90 calendar days, unless otherwise specified in the ad hoc request

The day of DLP is day 0 of the 70- or 90-calendar-day interval between the DLP and report
submission. Where national or regional requirements differ from the above, the MAHs should
discuss the timeline for submission with the relevant regulatory authority.

9. Format and presentation of PBRER

A. Format
The recommended format and content of the PBRER, including table of contents, section
numbering, and content of each section, are outlined below.
The full ICH Guideline E2C(R2) format should be used for all PBRERs. When no relevant
information is available or a PBRER section is not applicable, this should be stated. Particular
sections of the PBRER may share content with other regulatory reports, e.g., documents
described in ICH guidelines E2E and E2F.

B. Presentation

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The recommended format and content of the PBRER, including table of contents, section
numbering, and content of each section, are outlined below. All sections in the PBRER should
be completed. When no information is available, this should be stated.

Title Page
Executive Summary
Table of Contents
1 Introduction
2 Worldwide Marketing Approval 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 Tabulate
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 Period
7.1 Completed Clinical Trials
7.2 Ongoing Clinical Trials
7.3 Long-Term Follow-up
7.4 Other Therapeutic Use of Medicinal Products
7.5 New Safety Data Related to Fixed Combination Therapies
8 Findings from Non-Interventional Studies
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 of Signals: New, Ongoing, or Closed
16 Signal and Risk Evaluation
16.2 Summary of Safety Concerns
16.3 Signal Evaluation
16.3 Evaluation of Risks and New Information
16.4 Characterization of Risks
16.5 Effectiveness of Risk Minimization (if applicable)
17 Benefit Evaluation
17.1 Important Baseline Efficacy/Effectiveness Information
17.2 Newly Identified Information on Efficacy/Effectiveness
17.3 Characterization of Benefits
18 Integrated Benefit-Risk Analysis for Approved Indications
18.1 Benefit-Risk Context - Medical Need and Important Alternatives
18.2 Benefit-Risk Analysis Evaluation

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 19 Conclusions and Actions
20 Appendices

For further guidance on the format and content of a PBRER, please refer to the ICH E2C (R2)
Guideline on Periodic Benefit-Risk Evaluation Report (PBRER)

C. ANNEX for PBRER Submission

In case, emerging safety concern is specific in Thailand, MAHs may be requested to prepare
Thailand annex. An annex should be submitted together with the PBRER. It should provide
information specific to Thailand and include the following section.
i. Product overview in Thailand
ii. Summary of safety changes:
a. Action taken in the reporting interval for safety reasons
b. Changes in reference safety information (RSI)
c. Action(s) taken or planned in Thailand
iii. List of signals evaluated

i. Product Overview
MAHs should provide the following information describing the product’s character.

Date of submission DD/MM/20YY

Submission Number e.g. 1st submission
(Reporting interval) (DD/MM/20YY – DD/MM/20YY)
The rationale for PBRER
submission
Product Name
Active Ingredient(s)
Strength
Dosage form
Route of administration
Formulation(s)
Approved indication(s),
approval date
Mode (s) of action
Therapeutic class (es)
Drug registration No
MAHs name
MAHs address
Responsible person for Name
pharmacovigilance Designation
 QPPV Phone/Mobile
 CPPV Email
Date of 1st marketing DD/MM/20YY
authorized in Thailand
International birth date (IBD) DD/MM/YYYY

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 Product category e.g. New drug product/Biologics/ biosimilars/hybrid/
combination products / vaccines /ATMP /others
Estimated cumulative ……………….. subjects exposed in clinical trials
exposure of clinical trial Interval DD/MM/YYYY - DD/MM/YYYY
subjects; interval and ……………….. subjects exposed after drug approval
cumulative post-approval
exposure;
Number of countries in which ……… countries
the medicinal product is (name of the countries)
approved
Summary of overall benefit-
risk evaluation
Actions taken or proposed for e.g., significant changes to the reference product
safety reasons information, other risk minimization activities
Conclusions

ii. Summary of safety changes

A. Actions taken in the reporting interval for safety reasons
Brief tabulated summary of significant actions related to safety that have been taken in
any other countries during the reporting interval, relating to marketing experience by the
PRH, or authorities.

The suggested summary table for significant actions related to safety that have been
taken.

Action(s) taken Description of action(s) taken Status of the action(s) taken

by
Example MAHs was requested to include Updated US PI was approved on
US FDA liver injury in the warnings and DD/MM/YYYY.
precautions section of the US PI.

B. Changes in reference safety information (RSI)

Brief tabulated summary of changes in RSI during the reporting interval.
Changes in reference safety information (RSI) that have been taken during the reporting
interval.

Version (Date) Description of changes Applicable to Thailand

or not (Yes/No)
Example Warning and precaution section was Yes
Version 2 updated regarding the risk of liver injury
(DD/MM/YYYY)

C. Action(s) taken or planned in Thailand

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 MAHs should provide description of specific action(s); both safety action and reference
information, that have been taken or planned to implement in Thailand. The suggested
summary table should be filled out.
Type of action/plan Details
Safety-related
Non safety-related

iii. List of signals evaluated

To list all signals that were closed (e.g. the evaluation was completed) during the
reporting interval as well as ongoing signals that were undergoing evaluation, at the end
of reporting interval. The description(s) of the signal evaluations are not to be included
For office use only
Thai FDA reference No
Date received
Date assessed
Name of accessor
Remarks

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 Chapter 9 Post-Authorization Safety Study (PASS)

A post-authorization safety study (PASS) is a study that is carried out after a medicine has been authorized
to obtain further information on a medicine's safety or to measure the effectiveness of risk-management
measures.

The purpose of this chapter is to guide any organizations that involve PV functions and need to develop
the PASS to evaluate the safety and benefit-risk profile of medicinal products and support regulatory
decision-making. They aim to:

• identify, characterize or quantify a safety hazard

• confirm the safety profile of a medicine
• measure the effectiveness of risk-management measures

PASSs can either be clinical trials (intervention trials) or non-interventional studies.

Terminology

Date at which a study commences: date of the start of data collection.

Start of data collection: the date from which information on the first study subject is first recorded in the
study dataset or, in the case of secondary use of data, the date from which data extraction starts.

End of data collection: the date from which the analytical dataset is completely available.

Analytical dataset: the minimum set of data required to perform the statistical analyses leading to the
results for the primary objective(s) of the study.

Substantial amendment to the study protocol: amendment to the protocol likely to have an impact on
the safety, physical or mental well-being of the study participants or that may affect the study results and
their interpretation, such as changes to the primary or secondary objectives of the study, the study
population, the sample size, the study design, the data sources, the method of data collection, the
definitions of the main exposure, outcome and confounding variables or the statistical analytical plan as
described in the study protocol.

Structures and processes

Principles
A post-authorization study should be classified as a post-authorization safety study when the main aim
for initiating the study includes any of the following objectives:

• assess risks associated with a medicinal product, quantify incidence rate, compare to non-exposed
population, investigate risk factors and effect modifiers. to evaluate the risks of a medicinal
product used in a patient population for which safety information is limited or missing (e.g.
pregnant women, specific age groups, patients with renal or hepatic impairment or other relevant
comorbidity or co-medication)

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 • evaluate the risks of a medicinal product after long-term use
• provide evidence about the absence of risks
• Assess drug use patterns to gain insights into medicine safety and risk management effectiveness.
Collect information on indication, off-label use, dosage, co-medication, and errors. Conduct
studies to estimate the public health impact of safety issues.
• measure the effectiveness of risk management measures

Whereas the PASS design should be appropriate to address the study objective(s), the classification of a
post-authorization study as a PASS is not constrained by the type of design chosen if it fulfils the above
criteria. For example, a systematic literature review or a meta-analysis may be considered as PASS
depending on its aim.

All PASS should be conducted by qualified personnel (e.g. with appropriate education, training, and
experience). In addition, PASS shall not be performed where the act of conducting the study promotes
the use of a medicinal product.

The PASS proposal should include the following topics:

• rationale, main objectives, and brief description of the intended methods of the research to be
carried out by the investigator(s)
• rights and obligations of the investigator(s) and marketing authorization holders(MAHs)
• clear assignment of tasks and responsibilities
• procedure for achieving agreement on the study protocol
• provisions for meeting the marketing authorization holder’s pharmacovigilance obligations,
including the reporting of adverse reactions and other safety data by investigators, where
applicable
• intellectual property rights arising from the study and access to study data
• storage and availability of analytical dataset and statistical programs for audit and inspection
• communication strategy for the scheduled progress and final reports
• publication strategy of interim and final results

Study registration
To facilitate the governance of the pharmacovigilance activities between the NRAs and the MAHs, MAHs
should list all PASS in the risk management plan.

PASS protocol should be registered in the PASS registration website before the study commences or at
the earliest possible date, for example, if data collection had already started for a study included in the
risk management plan.

The study protocol should be uploaded as soon as possible after its finalization and prior to the start of
data collection. Updated study protocols in case of substantial amendments, progress reports and the
final study report should also be entered in the PASS registration database.

Study protocol

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PASS conducted either voluntarily or obligatory by the NRA, should have a written study protocol and
should be submitted to the NRA.

The study protocol should be developed by individuals with appropriate scientific background and
experience. Various study designs frequently used in PASS includes, but not excludes were:

• Active surveillance
o Intensive monitoring schemes
o Prescription event monitoring
o Registries
• Observational studies
o Cross-sectional study
o Cohort study
o Case control study
o Case only design
• Clinical trials
o Large simple trials
• Drug utilization studies

There are various sources of data to be used in the PASS.

• Primary data collection

o Interview
o Paper-based medical records
• Automated database
o Medical record e.g. diagnosis, prescription, payment
o Claim database
o Others e.g. referral information, discharge information

With any data source used, the privacy and confidentiality regulations that apply to personal data should
be adhered to.

A PASS should be revived and sigh-off by the qualified person responsible for pharmacovigilance (QPPV)
or the contact person for pharmacovigilance before PASS is submitted to the Thai FDA.

Format and content of the study protocol

It is suggested the PASS protocol should follow the following format.

1. Title: informative title should compose of term indicating the study design, medicinal product,
and a sub-title with a version identifier and the date of the last version.
2. Marketing authorization holder: name and address of the MAH.
3. Responsible parties: names, titles, qualifications, addresses, and affiliations of all main
responsible parties, including the main author(s) of the protocol, the principal investigator, a
coordinating investigator for each country in which the study is to be performed and other
relevant study sites. A list of all collaborating institutions and investigators should be made
available to the NARs upon request.

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4. Abstract: summary of the study protocol including the following sub-sections:
• Title with subtitles including version and date of the protocol and name and affiliation of
main author
• Rationale and background
• Research question and objectives
• Study design
• Population
• Variables
• Data sources
• Study size
• Data analysis
• Milestones.

5. Amendments and updates: MAHs should inform the NRAs of any substantial amendment and
update to the study protocol after the start of data collection. It should include:
• a justification for each amendment
• dates and a reference to the section where the change is made

6. Milestones: table with planned dates for the following milestones:

• Start of data collection
• End of data collection
• Study progress report(s)
• Final report of study results

Any other important timelines in the conduct of the study should be presented.

7. Rationale and background: Summarize the safety hazards that initiated the study, provide a
critical review of relevant published and unpublished data to explain gaps in knowledge, and cite
findings of similar studies. Additionally, highlight the expected contribution of the current study.

8. Research question and objectives: research question that explains how the study will address
the issue that led to the study being initiated, and research objectives, including any pre-specified
hypotheses and main summary measures.

9. Research methods: description of the research methods, including:

9.1. Study design:

▪ Overall research design and rationale for this choice.
9.2. Setting:
▪ Study population; eligibility criteria and the rationale for the criteria, time period
▪ Sampling method
▪ If the study is a systematic review or a meta-analysis, inclusion and exclusion
criteria should be explained

9.3. Variables:

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 ▪ Key variables such as outcomes, exposures and other covariates should be
specified.
▪ If the study requires feasibility or pilot studies carried out to support the
development of the protocol, for example, the testing of a questionnaire or
specify the operational definition of events or prescriptions, these details should
also be included in the report.

9.4. Data sources:

▪ Data sources for involved variables should be elaborated. Data collecting tools or
instruments should be elaborated. If reliability and validity of the instruments are
important, please also provide details.
9.5. Study size:
▪ Provide rationale to justify the minimally detectable sample size to ensure the
accuracy of the answer.
9.6. Data management:
▪ Data collection approach, data retrieval and preparation should be described
▪ Appropriate statistical tests should be mentioned.
▪ The study should consider data protection, privacy and anonymity.
9.7. Data analysis:
▪ Data cleaning, imputation of missing data, transformation or recode of data, data
categorization. Analysis plan and result presentation
▪ Procedure to control source of bias
▪ Statistical procedure to obtain point estimates and confidence intervals as well
as sensitivity analysis
▪ Primary analyses, secondary analyses, and sub-group analyses should be stated.
▪ Interim report should be provided (when appropriate)
9.8 Quality control:
▪ Accuracy and legibility of collected data and original documents
▪ Extent of source data verification
▪ Validation of endpoints
▪ Storage of records and archiving of statistical programs
▪ Certification and/or qualifications of laboratory or research groups should be
included, as appropriate
9.9. Limitations of the research methods:
▪ Potential limitations of the study design, data sources, and analytic methods,
including issues relating to confounding, bias, generalizability, and random error.
▪ The likely success of efforts taken to reduce errors should be discussed.
10. Protection of human subjects: safeguards to comply with national requirements for ensuring
the well-being and rights of participants in safety studies.
11. Management and reporting of adverse events/adverse reactions:
• The study should detail procedures for reporting suspected adverse reactions and other
medically important events that could affect the product's risk-benefit balance.
• In studies with safety data is not the primary data collection, MAHs should justify their
approach to safety data collection. Use the appropriate MedDRA classification for

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 uncollected adverse events. Include channels for reporting suspected reactions. Fatal
reactions not subject to expedited reporting should be listed in a table with a rationale.
• When conducting studies based on secondary use of data, it is important to mention in a
statement whether adverse events or adverse reactions are analyzed. If they are being
analyzed, they should be specified using the appropriate level of the MedDRA
classification. It is not necessary to report suspected adverse reactions in the form of
individual case safety reports.
• For combined study designs, the same requirements as for studies with primary data
collection should be followed for adverse events obtained through primary data
collection and the guidance for studies with design based on secondary use of data should
be applied to adverse events based on secondary data collection.

12. Plans for disseminating and communicating study results, including any plans for submission
of progress reports and final reports
13. References

Substantial protocol amendments

• The study protocol should be amended and updated as needed. Any substantial amendments
to the protocol after the study starts should be documented in the protocol in a traceable and
auditable way, including the dates of the changes.
• If changes to the protocol lead to the study being considered either an interventional clinical
trial or a non-interventional PASS, NRA should be informed before implementation.

Reporting of pharmacovigilance data to NRAs

1. Data relevant to the risk-benefit balance of the product

MAHs should monitor study data and report any new information affecting the risk-benefit
balance of a medicinal product to the Thai FDA as an emerging safety issue in writing. This includes
adverse reaction analysis and aggregated data.
This communication is without prejudice to the information on the findings of studies, which
should be provided by means of periodic benefit-risk evaluation reports (PBRER) and in the RMP
updates, where applicable.

2. Reporting of adverse reactions/adverse events

Report individual cases of adverse reactions to the Thai FDA. Summarize adverse events in interim
and final study reports for both primary and secondary data collection unless protocol allows for
different reporting with justification.
Procedures for collecting, managing, and reporting suspected adverse reactions should be
outlined in the study protocol. Refer to the pharmacovigilance system master file if necessary,
but include study-specific details in the study protocol.

3. Study reports
a. Progress report and interim report of study results

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The progress report documents study progress, including patient numbers, outcomes, issues, and
deviations from the expected plan. It may also include interim study results.
The interim report should include planned interim analysis findings. A progress report for PASS
should be submitted to Thai FDA. Timing should be agreed in the study protocol.

b. Final study report

A final report of the PASS conducted per regulatory commitment should be submitted within 12
months of data collection completion. Even if the study is discontinued, a final report should be
submitted, along with the reasons for termination.

The final study report should include the following information:

1. Title: include the study design; sub-titles with the date of the final report and name and
affiliation of the main author, and study registration number (if applicable).
2. Abstract: It should be composed of
1. Title, with subtitles including date of the abstract and name and affiliation of main
author
2. Keywords (not more than five keywords indicating the main study characteristics)
3. Rationale and background
4. Research question and objectives
5. Study design
6. Setting
7. Subjects and study size (including dropouts)
8. Variables and data sources
9. Results
10. Discussion (including an evaluation of the impact of results on the risk-benefit balance
of the product)
11. Conclusion
12. Marketing authorization holder
13. Names and affiliations of principal investigators.
3. Marketing authorization holder: Provide the name and address of the MAH.
4. Investigators: Provide the following investigators’ detail
• names, titles, degrees, addresses, and affiliations of the principal investigator and all
co-investigators,
• list of all collaborating primary institutions and other relevant study sites in all
relevant countries
• list of all collaborating institutions and investigators
5. Milestones: Key milestone dates should be provided:
• Start of data collection (planned and actual dates)
• End of data collection (planned and actual dates) or date of early termination, if
applicable, with reasons for termination
• Study progress report(s)
• Interim report(s) of study results, where applicable
• Final report of study results (planned and actual date)

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 • Any other important milestone applicable to the study, including date of study
registration and date of protocol approval by an Institutional Review
Board/Independent Ethics Committee if applicable.

6. Rationale and background: description of the safety concerns that led to the study being
initiated or imposed, and critical review of relevant published and unpublished data evaluating
pertinent information and gaps in knowledge that the study is intended to fill.
7. Research question and objectives: research question and research objectives, including any
pre-specified hypotheses, as stated in the study protocol.
8. Amendments and updates to the protocol: list of any substantial amendments and updates to
the initial study protocol after the start of data collection, including a justification for each
amendment or update.
9. Research methods:
9.1. Study design: key elements of the study design and the rationale for this choice.
9.2. Setting: setting, locations, and relevant dates for the study, including periods of
recruitment, follow-up, and data collection. In case of a systematic review or meta-
analysis, study characteristics used as criteria for eligibility, with rationale.
9.3. Subjects: any source population and eligibility criteria of study subjects. Sources and
methods of selection of participants should be provided, including, where relevant
methods for case ascertainment, as well as number of and reasons for dropouts.
9.4. Variables: all outcomes, exposures, predictors, potential confounders, and effect
modifiers, including operational definitions and diagnostic criteria, if applicable.
9.5. Data sources and measurement: for each variable of interest, sources of data and
details of methods of assessment and measurement. If the study has used an existing data
source,

such as electronic health records, any information on the validity of the recording and
coding of the data should be reported. In case of a systematic review or meta-analysis,
description of all information sources, search strategy, methods for selecting studies,
methods of data extraction and any processes for obtaining or confirming data from
investigators.
9.6. Bias: any efforts to assess and address potential sources of bias at the design stage.
9.7. Study size: study size, rationale for any study size calculation and any method for
attaining projected study size.
9.8. Data transformation: transformations, calculations or operations on the data,
including how quantitative data were handled in the analyses and which groupings were
chosen and why.
9.9. Statistical methods: description of the following items:
• Main summary measures
• All statistical methods applied to the study, including those used to control for
confounding and, for meta-analyses, methods for combining results of studies
• Any methods used to examine subgroups and interactions
• How missing data were addressed

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 • Any sensitivity analyses
• Any amendment to the plan of data analysis included in the study protocol, with
a rationale for the change.
9.10. Quality control: mechanisms to ensure data quality and integrity.
10. Results: presentation of tables, graphs, and illustrations to present the pertinent data and
reflect on the analyses performed. Both unadjusted and adjusted results should be presented.
The precision of estimates should be quantified using confidence intervals. This section should
include the following sub-sections:
10.1. Participants: numbers of study subjects at each stage of study, e.g. numbers
potentially eligible, examined for eligibility, confirmed eligible, included in the study,
completing follow-up, and analyzed, and reasons for non-participation at any stage.
In the case of a systematic review or meta-analysis, a number of studies screened,
assessed for eligibility and included in the review with reasons for exclusion at each
stage.
10.2. Descriptive data: characteristics of study participants, information on exposures
and potential confounders and number of participants with missing data for each
variable of interest. In case of a systematic review or meta-analysis, characteristics of
each study from which data were extracted (e.g. study size, follow-up).
10.3. Outcome data: numbers of participants across categories of main outcomes.
10.4. Main results: unadjusted estimates and, if applicable, confounder-adjusted
estimates and their precision (e.g. 95% confidence interval). If relevant, estimates of
relative risk should be translated into absolute risk for a meaningful time period.
10.5. Other analyses: other analyses done, e.g. analyses of subgroups and interactions,
and sensitivity analyses.
10.6. Adverse events and adverse reactions: summary of all adverse events/adverse
reactions collected in the study, in line with regulatory requirements
11. Discussion:
11.1. Key results: key results with reference to the study objectives, prior research in
support of and conflicting with the findings of the completed post-authorization
safety study, and, where relevant, impact of the results on the risk-benefit balance of
the product.
11.2. Limitations: The study has limitations that include potential data quality or integrity
issues, limitations of the study approach, potential sources of bias and imprecision,
and validation of the events. These limitations should be discussed, and their
direction and magnitude should be clearly stated.
11.3.Interpretation: interpretation of results considering objectives, limitations,
multiplicity of analyses, results from similar studies and other relevant evidence.
11.4. Generalizability: the generalizability (external validity) of the study results.
12. Other information: any additional or complementary information on specific aspects not
previously addressed.
13. Conclusions: The main conclusions of the study derive from the analysis of the data.
14. References.

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 Publication of study results
For studies led by non-employee investigators, a pre-established publication policy between the MAHs
and investigator is necessary. This policy should clearly state whether the principal investigator has the
authority to publish the study results, regardless of data ownership. Before manuscript submission, the
MAHs has the right to review the results and interpretations included in the manuscript and offer
comments.

• Submission of manuscripts accepted for publication

To allow NRAs to review in advance the results and interpretations to be published, the MAHs
initiating, managing, or financing a PASS should communicate to the NRAs the final manuscript of
the article within the appropriate timeline after first acceptance for publication.

Data protection
The MAHs and investigators should follow relevant data protection regulations to ensure that the
individual’s data is protected and kept confidential.

Quality systems, audits and inspections

The MAHs should ensure the fulfillment of their PV obligations in relation to the study and that this can
be audited, inspected, and verified. For PASS imposed as an obligation, the MAHs should ensure that the
analytical dataset and statistical programs used for generating the data included in the final study report
are kept in electronic format and are available for auditing and inspection.

Impact on the risk management system

Information on PASS conducted pursuant to an obligation imposed by an NRAs or required in the risk
management plan should be included in the RMP.

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Methods for post-authorization safety studies
Study designs
Adopting an appropriate study design depends on the objective of the post-authorization safety studies.
Reliability and accuracy of PASS result depends greatly on the study design and source of data. For more
information regarding the PASS methodology, MAHs should refer to the ENCePP Guide for
Methodological Standards in Pharmacoepidemiology
(https://www.encepp.eu/standards_and_guidances/methodologicalGuide.shtml).

1. Active surveillance
Active surveillance is an organized process that aims to thoroughly identify the number of adverse events
(AE) in a defined population exposed to a certain medicine. In general, active surveillance is a practical
way to collect adverse event data within a quantified population. Although active surveillance may result
in a higher number of reported adverse events, situations such as delayed adverse events may introduce
bias to the incidence reporting.
1.1 Intensive monitoring schemes
Description: Intensive monitoring involves gathering records in specific settings, like hospital units or
within community practice, through designated healthcare professionals. Some settings are selected as
sentinel sites. Specified major events that are likely medicine-related events, such as hepatic disorders,
renal failure, hematological disorders, or bleeding, will be the focus of the study. Intensive monitoring
could involve data collection from specific patient subgroups, e.g., the elderly, the young, and pregnancy.
Data source: Various data sources can be used such as
• Medical records
• Interviewing patients, physicians, nurses, pharmacists
Expected outcome: AE case report
Pros: Number of AE reports (case series)
Cons: The outcome may or may not be a good representative. It depends on
1) How the sentinel sites are selected.
2) Potential selection bias
3) Unavailable or missing adverse events data in the source data.
4) Reported rate within the sentinel sites.
Success factor: The organization should ensure that the responsible staffs are trained. They thoroughly
understand the data collection and reporting process.

1.2. Prescription event monitoring

Description: Prescription event monitoring focused on observing the adverse event from patients who
took the medicine of interest in a pre-defined health care facility setting.
Data source: Various data sources can be used such as
- electronic prescription data or automated health insurance claims
- follow up a questionnaire among patients or physicians at pre-specified intervals.
Expected outcome: Incident rate = number of AE/number of patients who used this product
Pros: Incident rate can be observed.
Appropriate for observing AE of new drug product in a short period of time. Other information can be
collected e.g. patient demographic, indication for treatment, starting date, strength of drug, exposed
duration, reason for discontinuing the medicine.
Cons: 1. Potential loss follow-up during the observation period. 2) May miss delayed AEs as too short
follow-up duration
Success factor: Good IT system

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 1.3. Registries
Description: A registry is an organized system that uses observational methods to collect uniform data on
specified outcomes in a defined population, e.g., patients with certain diseases prescribed with medicine
of interest. Registries are particularly useful when dealing with a rare disease, rare exposure or special
population.
Registry data: Contain characteristics of patients, disease, medicine utilization patterns, and treatment
outcome; patient-reported outcome, clinical conditions, and safety.
Expected outcome: Incident rate = number of AE/number of patients who used this medicine.
Pros: It’s a prospective study. Registry protocol can be planned. Required data can be collected.
The registry can be useful for signal amplification, particularly for rare outcomes. Registries can be used
to address exposure to medicinal products in specific populations, such as pregnant women.
Cons: No comparison among those not exposed to the drug of interest.

2. Observational studies
Various epidemiological methods are employed to assess and determine the association between adverse
events and exposure to medication. The commonly used methods include cross-sectional studies, case-
control studies, and cohort studies.
2.1. Cross-sectional study
Description: The design is a cross-sectional which means both exposure status and adverse events are
collected at one point in time.
Data source: Physician or patient interview or database in a defined interval.
Expected outcome: Crude or preliminary association for exposure-adverse event
Pros: Easy to conduct, fast
Cons: Cannot capture temporal relationship between exposure and outcome.
2.2. Cohort Study
Description: The study design is prospective. Participants are divided into those who are exposed and
those who are not exposed to the medicine of interest. They are followed up to observe whether adverse
events of interest occur within a defined timeline.
Data source: Patient identification can be done using the automated database.
Expected outcome: Incident rate and relative risk.
Pros: Ensure temporal order. Can evaluation of multiple adverse events within the same study.
Cons: Not suitable for rare exposure. Not suitable for AE that takes time to develop.

2.3. Case-control study

Description: The design is retrospective. It starts with identifying cases (those with AEs of interest) and
controls (those without AEs of interest) and retrospectively evaluate whether they had exposed to the
medicine of interest or not.
Data source: Patient identification can be done using the existing database or using a field study
approach.
Expected outcome: incident rate and relative risk.
Pros: Suitable for rare AEs. Less time consuming when compared to a cohort study.
Cons: Provide estimation of drug-AE association because the design does not guarantee temporal order.

2.4. Case-only designs

Description: Case-only designs have been proposed to assess the association between intermittent
exposures and short-term events, including the self-controlled case-series, the case-crossover and the

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case-time-control studies. In these designs, only cases are used and the control information is obtained
from person-time experience of the cases themselves.
Data source: Patient identification can be done using the existing database or using a field study approach
Expected outcome: Estimate a relative incidence, that is, incidence rates within the risk window(s) after
exposure relative to incidence rates within the control window(s)
Pros: Because the design is self-controlled, the confounding factors were automatically matched.
Cons: Case-only design may not be appropriate when the AE onset is difficult to establish or when
evaluating chronic exposure.

3. Clinical trials
MAHs may be asked to conduct additional clinical trials to ensure safety and efficacy in a broader
population group or to provide details of the mechanism of action for certain ADRs.
3.1. Large simple trials
Description: Large simple trials or pragmatic trials are a form of clinical trials conducted in a large number
of patients that are randomized into treatment and non-treatment groups. The patients will be followed
up, but with a minimal follow-up schedule to reduce the burden.
Data source: Field study and/or medical database
Expected outcome: Incident rate and relative risk.
Pros: Temporal order can be identified. The large sample size clinical trial covered a broader population
who were previously excluded from well-controlled studies
Cons: high cost, time consuming, and loss follow up for prospectively study design.
4. Drug utilization studies
Description: The scope of drug utilization studies (DUS) involves a description of how target medicine is
used in routine clinical practice in large populations. Also, specific groups of populations, such as the
elderly, children, or patients with hepatic dysfunction, are usually excluded from clinical trials. It is usually
used to evaluate the effect of interventions such as regulatory actions, media attention on specific
medicine, extent of off-label use, etc.
Data source: Prescription database, claim database
Expected outcome: target drug utilization pattern.
Pros: Can analyze both general population and special population subgroups.
Cons: Because of the descriptive nature, DUS may not well capture drug-AE association. The breath of
analysis depends on the quality of the data.

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 Chapter 10 Signal Management

Pharmacovigilance aims to ensure patient safety. National pharmacovigilance centers or Marketing

authorization holders need to screen and detect any harm caused by medicines early on. Signal detection
is crucial for achieving this objective. Effective communication of signals is necessary for minimizing harm,
a primary goal of pharmacovigilance.

This chapter aims to guide any organizations who are involved in PV function on the direction of signal
management, particularly in organizations with restricted databases and resources. Typically, in such
scenarios, the quantity of individual case safety reports (ICSRs) will be relatively low, and the range of
medicinal products and event profiles may be specific to the location.

Signal
A signal is a hypothesis of risk associated with a medicine, based on data from one or more sources and
supporting arguments. Signal may be a new causal association arising from observations or experiments.
It may reveal new aspects of known associations that are adverse or beneficial, including changes in
frequency, distribution, duration, severity, or outcome. Signals apply to medicinal products containing the
same active substance, including combination products. They may be relevant to a specific medicinal
product or indication, strength, pharmaceutical form, or route of administration, or a whole class of
medicinal products.

Signal management process:

The process of evaluating individual case safety reports (ICSRs), data from passive or active surveillance
systems, scientific literature, and other sources to determine if there are any new risks associated with a
medicinal product or active substance, or if any known risks have changed. This includes making
recommendations and decisions and communicating any findings, as well as tracking the outcomes of
these actions.
The signal management process includes the following activities:
• signal detection,
• signal validation,
• signal confirmation,
• signal analysis and prioritization,
• signal assessment, and recommendation for action.

Structures and processes

1. Sources of data
Signals can come from various sources including scientific data related to medicinal product use and
outcomes. These sources include spontaneous reporting systems, active surveillance systems, studies,
digital media, national regulatory safety databases, and scientific literature. Adverse reaction
databases are periodically monitored to detect signals, which can vary in size and scope. This chapter
focuses on signals from spontaneous reporting systems, but all relevant sources should be considered
during signal management. These sources may be included ;
• MAHs safety database
• Health Product Vigilance Centers (HPVC) database
• Public Health program database

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 • WHO VigiLyze database
• Clinical trials
• Regulatory websites & newsletters
• WHO pharmaceutical newsletters
• Scientific Meeting
• Scientific literature
• Traditional and social media

2. Signal detection
Signal detection requires a specific methodology considering the nature of data and characteristics of
medicinal products. All relevant data should be considered, and clinical judgment applied. Signal
detection may involve a review of ICSRs, statistical analyses or both. Organizations should document
the process adequately.

In pharmacovigilance systems that rely on spontaneous reporting, there are two types of signal
detection methodology.
• The qualitative method involves a manual screening process, followed by a medical review
of individual case safety reports (ICSRs) or a review of a series of cases.
• The quantitative (statistical) method screens the database by using simple cross-tabulations
for disproportionality or using data-mining algorithms. Their goal is to identify
disproportionality when the number of reports of a suspected drug-ADR combination is
higher than expected. Disproportionality analysis will help for hypothesis generation, not for
hypothesis testing. After discovering disproportionality, medical experts review individual
case safety reports and case series.

Organizations with small databases are less amenable to data mining techniques, and flagging issues
of interest when any kind of ADR report is first received is the best way to identify potential signals.

3. Signal validation
The review of ICSR data should consider these elements for signal validation.
• Previous awareness
o Adverse reaction is already included in the product information (summary of product
characteristics (SmPC) and package leaflet;
o Signal /adverse reaction already known in the SmPC for other medicinal products
containing the active substance of interest,
o the association has already been assessed in the initial application for marketing
authorization, the risk management plan (RMP), the periodic safety update report
(PSUR)
• Strength of the evidence
o total number of possibly related cases (exclusion of duplicates)
o number of cases per patient exposure (prevalence/incidence)
o additional cases reported with related terms (other MedDRA terms indicating clinical
complications of the same reaction)
o consistency of the evidence across cases (characteristics of cases)
o quality of the data and their documentation
o cases matching internationally agreed case definitions if applicable (such as Brighton
Collaboration case definitions for vaccine, RegiSCAR criteria for severe cutaneous
adverse reactions 10 http://www.regiscar.org/ )

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 o causality assessment at possible and above (dose-reaction, temporal relationship,
and other confounding factors)
o biological mechanism and pharmacological plausibility
o case pooling (case series) analysis
o disproportionality of reporting, if applicable.
• Other clinical contexts
o seriousness and severity of the reaction
o outcome and reversibility of the reaction
o additional insight on a known adverse reaction included severity, duration, outcome,
incidence, or management
o reactions in drug-drug interactions
o reactions in vulnerable populations (such as pregnant women, children, or the older
population, or in patients with pre-existing risk factors)
o reactions in different patterns of use (overdose, abuse, misuse, off-label use,
medication errors, falsified products);

The signal management process within organizations demonstrated in figure 1 can include multiple expert
discussions and decision-making levels, resulting in different outcomes. It's important to document any
decision trees as part of the signal management process description.

figure 1 Signal management process

propose risk
new or changed
minimization
risk
activities
further
signal validated
assessment
signal detection signal validation refuted signal
non-validated
signal

4. Signal prioritization
During the signal management process, organizations should evaluate whether signals imply risks that
could significantly affect patients' or public health and/or the risk-benefit balance of the medicinal
product. The following should be considered when evaluating this impact:
• severity, seriousness, outcome, and reversibility and the potential for prevention
• patient exposure and frequency of adverse reaction
• exposure in vulnerable populations and/or in populations with different patterns of use,
• consequences of discontinuation of the disease under treatment and the availability of other
options
• expected regulatory intervention (addition of adverse reactions, warnings, contraindications,
additional risk minimization measures, suspension, revocation)
• apply to other substances of same class of medicinal products.
• media attention and/or public concerns (adverse events on mass immunization)
• urgency for further signal management (depending on the prioritization)

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 • appropriate timely measures at any stage once the information is available
• clinical judgment and flexibility throughout the process.

Quality requirements
• Develop, document, and implement the process for managing signals, including the rationale for
the method, periodicity of signal detection, tracking system activities, and process control for all
steps.
• MAHs should describe their signal management process in the Pharmacovigilance System Master
File and monitor system performance with performance indicators in the annex.
• MAHs should implement a record management system for pharmacovigilance documents. This
system should ensure easy retrieval and traceability of measures taken, investigation timelines,
and safety decisions.
• It is important to conduct regular audits of signal management activities, just as with any critical
process. This ensures that any errors in the process can be identified and corrected in a timely
manner.
• Ensure confidentiality, security, and validity of data and documents as per applicable laws and
regulations, including data integrity during inter-organizational transfers.

Role of MAHs
• MAHs should continually monitor product safety and promptly inform authorities of any new
safety information that may affect marketing authorization.
• During a product's lifecycle, it is recommended to analyze signals from other sources, including
the HPVC database etc.
• It is recommended to monitor the HPVC database at least every 6 months. More frequent
monitoring is advised for active substances in medicinal products on the additional monitoring
list.

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 REFERENCES

1. World Health Organization (WHO). The importance of pharmacovigilance: safety monitoring of

medicinal products. Genève: WHO; 2002 https://www.who.int/publications-detail-redirect/10665-
42493

2. European Medicines Agency(EMA) Guideline on good pharmacovigilance practices (GVP) Module I –

Pharmacovigilance systems and their quality systems 2012
https://www.ema.europa.eu/documents/scientific-guideline/guideline-good-pharmacovigilance-
practices-module-i-pharmacovigilance-systems-their-quality-systems_en.pdf

3. European Medicines Agency(EMA) Guideline on good pharmacovigilance practices (GVP) Module II –

Pharmacovigilance system master file 2017 https://www.ema.europa.eu/documents/scientific-
guideline/guideline-good-pharmacovigilance-practices-module-ii-pharmacovigilance-system-master-
file-rev-2_en.pdf

4. European Medicines Agency(EMA) Guideline on good pharmacovigilance practices (GVP) Module III
– Pharmacovigilance inspections 2014 https://www.ema.europa.eu/documents/scientific-
guideline/guideline-good-pharmacovigilance-practices-module-iii-pharmacovigilance-
inspections_en.pdf

5. European Medicines Agency(EMA) Guideline on good pharmacovigilance practices (GVP) Module IV

– Pharmacovigilance audits 2015 https://www.ema.europa.eu/documents/scientific-
guideline/guideline-good-pharmacovigilance-practices-gvp-module-iv-pharmacovigilance-audits-
rev-1_en.pdf

6. European Medicines Agency(EMA) Guideline on good pharmacovigilance practices (GVP) Module V –

Risk management systems 2017 https://www.ema.europa.eu/documents/scientific-
guideline/guideline-good-pharmacovigilance-practices-module-v-risk-management-systems-rev-
2_en.pdf

7. European Medicines Agency(EMA) Guideline on good pharmacovigilance practices (GVP) Module VI

Collection, management, and submission of reports of suspected adverse reactions to medicinal
products 2017 https://www.ema.europa.eu/documents/regulatory-procedural-guideline/guideline-
good-pharmacovigilance-practices-gvp-module-vi-collection-management-submission-
reports_en.pdf

8. European Medicines Agency(EMA) Guideline on good pharmacovigilance practices (GVP) Module VI

Addendum I – Duplicate management of suspected adverse reaction reports 2017
https://www.ema.europa.eu/documents/regulatory-procedural-guideline/guideline-good-
pharmacovigilance-practices-gvp-module-vi-addendum-i-duplicate-management-suspected_en.pdf

9. European Medicines Agency(EMA) Guideline on good pharmacovigilance practices (GVP) Module VII
– Periodic safety update report 2013 https://www.ema.europa.eu/documents/scientific-
guideline/guideline-good-pharmacovigilance-practices-gvp-module-vii-periodic-safety-update-
report_en.pdf

103
10. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module VII
– Periodic safety update report 2013 https://www.ema.europa.eu/documents/scientific-
guideline/guideline-good-pharmacovigilance-practices-gvp-module-vii-periodic-safety-update-
report_en.pdf

11. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module
VIII – Post-authorization safety studies 2017 https://www.ema.europa.eu/documents/scientific-
guideline/guideline-good-pharmacovigilance-practices-gvp-module-viii-post-authorisation-safety-
studies-rev-3_en.pdf

12. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module
VIII Addendum I - Requirements and recommendations for the submission of information on non-
interventional post-authorization safety studies 2020
https://www.ema.europa.eu/documents/scientific-guideline/guideline-good-pharmacovigilance-
practices-gvp-module-viii-addendum-i-requirements-recommendations_en-1.pdf

13. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module IX
– Signal management 2017 https://www.ema.europa.eu/documents/scientific-guideline/guideline-
good-pharmacovigilance-practices-gvp-module-ix-signal-management-rev-1_en.pdf

14. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module IX
Addendum I – Methodological aspects of signal detection from spontaneous reports of suspected
adverse reactions 2017 https://www.ema.europa.eu/documents/scientific-guideline/guideline-
good-pharmacovigilance-practices-gvp-module-ix-addendum-i-methodological-aspects-
signal_en.pdf

15. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module X
– Additional monitoring 2013 https://www.ema.europa.eu/documents/scientific-
guideline/guideline-good-pharmacovigilance-practices-module-x-additional-monitoring_en.pdf

16. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module
XV – Safety communication 2017 https://www.ema.europa.eu/documents/scientific-
guideline/guideline-good-pharmacovigilance-practices-module-xv-safety-communication-rev-
1_en.pdf

17. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module
XVI – Risk minimization measures: selection of tools and effectiveness indicators 2017
https://www.ema.europa.eu/documents/scientific-guideline/guideline-good-pharmacovigilance-
practices-module-xvi-risk-minimisation-measures-selection-tools_en-3.pdf

18. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module
XVI Addendum I – Educational materials https://www.ema.europa.eu/documents/regulatory-
procedural-guideline/guideline-good-pharmacovigilance-practices-gvp-module-xvi-addendum-i-
educational-materials_en.pdf

104
19. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Annex I
definitions 2017 https://www.ema.europa.eu/documents/scientific-guideline/guideline-good-
pharmacovigilance-practices-annex-i-definitions-rev-4_en.pdf

20. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module
XVI risk minimization measures tools: selections of tools and effectiveness indicator 2021
https://www.ema.europa.eu/documents/regulatory-procedural-guideline/guideline-good-
pharmacovigilance-practices-gvp-module-xvi-risk-minimisation-measures-selection-tools_en.pdf

21. European Medicines Agency (EMA) Guideline on good pharmacovigilance practices (GVP) Module
XVI addendum II method for effectiveness evaluation 2021
https://www.ema.europa.eu/documents/regulatory-procedural-guideline/guideline-good-
pharmacovigilance-practices-gvp-module-xvi-addendum-ii-methods-effectiveness_en.pdf

22. International conference on harmonization of technical requirements for registration of

pharmaceuticals for human use guideline (ICH) E2A: Clinical safety data management: Definitions
and standards for expedited reporting 1995 https://www.ema.europa.eu/documents/scientific-
guideline/international-conference-harmonisation-technical-requirements-registration-
pharmaceuticals-human-use_en-15.pdf

23. International Conference on Harmonization of Technical Requirements for Registration of

Pharmaceuticals for Human Use guideline (ICH) E2B: Electronic transmission of individual case safety
reports (ICSRs) 2013 https://www.ema.europa.eu/documents/scientific-guideline/international-
conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-
4.pdf

24. International conference on harmonization of technical requirements for registration of

pharmaceuticals for human use guideline (ICH) E2B : questions and answers: data elements for
transmission of individual case safety report 2016
https://www.ema.europa.eu/documents/scientific-guideline/international-conference-
harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-18.pdf

25. International Conference on Harmonization of Technical Requirements for Registration of

Pharmaceuticals for Human Use guideline (ICH) E2C on periodic benefit-risk evaluation report 2013
https://www.ema.europa.eu/documents/regulatory-procedural-guideline/international-conference-
harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-0.pdf

26. International Conference on Harmonization of Technical Requirements for Registration of

Pharmaceuticals for Human Use (ICH) E2D: Post approval safety data management 2004
https://www.ema.europa.eu/documents/scientific-guideline/international-conference-
harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-12.pdf

27. International Conference on Harmonization of Technical Requirements for Registration of

Pharmaceuticals for Human Use (ICH) E2E: Pharmacovigilance planning 2005
https://www.ema.europa.eu/documents/scientific-guideline/international-conference-
harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-25.pdf

105
28. International Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) E2F on development safety update report – 2011
https://www.ema.europa.eu/documents/scientific-guideline/ich-guideline-e2f-development-safety-
update-report-step-5_en.pdf

29. European Union procedure on the preparation, conduct and reporting of EU pharmacovigilance
inspections 2014 https://www.ema.europa.eu/en/documents/regulatory-procedural-
guideline/union-procedure-preparation-conduct-reporting-eu-pharmacovigilance-
inspections_en.pdf

30. European Union guidance on record keeping and archiving of documents obtained or resulting from
pharmacovigilance inspections 2022 https://www.ema.europa.eu/en/documents/regulatory-
procedural-guideline/union-guidance-record-keeping-archiving-documents-obtained-resulting-
pharmacovigilance-inspections_en-1.pdf

31. European Medicines Agency(EMA) Good Practice Guide on Recording, Coding, Reporting and
Assessment of Medication Errors 2015 https://www.ema.europa.eu/en/documents/regulatory-
procedural-guideline/good-practice-guide-recording-coding-reporting-assessment-medication-
errors_en.pdf

32. European Medicines Agency(EMA) Guidance on the format of the risk management plan (RMP) in
the EU – in integrated format 2018 https://www.ema.europa.eu/en/documents/regulatory-
procedural-guideline/guidance-format-risk-management-plan-rmp-eu-integrated-format-rev-
201_en.pdf

33. European Medicines Agency(EMA) Individual Case Safety Report (ICSR) Implementation Guide 2021
https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/european-union-
individual-case-safety-report-icsr-implementation-guide_en.pdf

34. U.S. Food and drug administration (FDA) guidance for industry ; Good pharmacovigilance practices
and pharmacoepidemiologic assessment 2005 https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/good-pharmacovigilance-practices-and-pharmacoepidemiologic-
assessment

35. U.S. Food and drug administration (FDA) Guidance for Industry; E2E Pharmacovigilance Planning
2005 https://www.fda.gov/media/71238/download

36. U.S. Food and drug administration (FDA) Guidance for Industry; Development and Use of Risk
Minimization Action Plans 2005
https://www.fda.gov/media/71268/download

37. U.S. Food and drug administration (FDA) Guidance for Industry; REMS: FDA’s Application of
Statutory Factors in Determining When a REMS Is Necessary 2019
https://www.fda.gov/media/100307/download

106
38. U.S. Food and drug administration (FDA) Guidance for Industry ; Format and Content of a REMS
Document 2023 https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/format-and-content-rems-document-guidance-industry

39. U.S. Food and drug administration (FDA) Guidance for Industry; Risk Evaluation and Mitigation
Strategies: Modifications and Revisions 2020 https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/risk-evaluation-and-mitigation-strategies-modifications-and-revisions-
guidance-industry

40. U.S. Food and drug administration (FDA) Medication Guides — Distribution Requirements and
Inclusion in Risk Evaluation and Mitigation Strategies (REMS) 2011 https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/medication-guides-distribution-requirements-and-
inclusion-risk-evaluation-and-mitigation-strategies

41. U.S. Food and drug administration (FDA) Guidance for Industry ; Providing Regulatory Submissions
in Electronic Format — Content of the Risk Evaluation and Mitigation Strategies Document Using
Structured Product Labeling 2020 https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/providing-regulatory-submissions-electronic-format-content-risk-evaluation-
and-mitigation-strategies

42. U.S. Food and drug administration (FDA) Guidance for Industry ; Assessment for New Drug and
Biological Products 2023 https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/benefit-risk-assessment-new-drug-and-biological-products

43. Signal detection for national pharmacovigilance centers with small data sets, Uppsala Monitoring
Centre, WHO Collaborating Centre for International Drug Monitoring 2020
http://bit.ly/SmallDataSets

44. Council for International Organizations of Medical Sciences (CIOMS). Definition and application of
terms of vaccine pharmacovigilance (report of CIOMS/WHO Working Group on Vaccine
Pharmacovigilance). Genève: CIOMS; 2012 https://cioms.ch/wp-
content/uploads/2017/01/report_working_group_on_vaccine_LR.pdf

45. Council for International Organizations of Medical Sciences (CIOMS). Practical aspects of signal
detection in pharmacovigilance (report of CIOMS Working Group VIII). Genève: CIOMS; 2010.
https://cioms.ch/publications/product/practical-aspects-of-signal-detection-in-pharmacovigilance-
report-of-cioms-working-group-viii/

46. Health product vigilance center (HPVC), Thai food and drug administration (Thai FDA) guidance for
marketing authorization holders on post-marketing safety reporting of human drug, biological
product, narcotic drug and psychotropic substances and medicinal neuropsychotropic substance
2015
https://hpvcth.fda.moph.go.th/wp-content/uploads/file_atth_2020/hpvc_1_2_0_100691.pdf

107
47. Health product vigilance center (HPVC), Thai food and drug administration (Thai FDA) guidance for
government agency on safety reporting of medicinal products under imported or self production
condition 2022 https://hpvcth.fda.moph.go.th/ae-reporting-guidelines-for-government-agencies/

48. Food and drug administration of Thailand (Thai FDA) guidance on safety reporting of herbal
medicinal products 2022
https://herbal.fda.moph.go.th/media.php?id=486802799280136192&name=law_herbal3-
30%20%281%29.PDF

49. Surveillance and Response Guideline for Adverse Events Following Immunization, Department of
Disease Control (DDC), Ministry of Health, Thailand 2020.
https://ddc.moph.go.th/doe/journal_detail.php?deptcode=doe&publish=10663

50. Food and drug administration of Thailand (Thai FDA) guidance on conditional approval for
emergency use of Medicinal Products 2023
https://drug.fda.moph.go.th/media.php?id=526421589605097472&name=177%20FDA-
20230516.pdf

51. Food and drug administration of Thailand (Thai FDA) guidance on Advance Therapy Medicinal
Products (ATMPs ) 2022
https://drug.fda.moph.go.th/media.php?id=526421587541499904&name=174%20FDA-
20230116.pdf

52. Drug Act Thailand 1967

https://www.pharmacycouncil.org/index.php?option=content_detail&menuid=70&itemid=2514&ca
tid=0

53. Thai food and drug administration (Thai FDA) guidance of risk management plan for biologic
products 2017 https://hpvcth.fda.moph.go.th/wp-
content/uploads/file_atth_2020/hpvc_1_2_0_100707.pdf

54. Food and drug administration of Thailand (Thai FDA) guidance on Replacement on Safety
Monitoring Program with Risk Management Plan 2023
https://drug.fda.moph.go.th/announcement-drug-division/a20230915/

55. Food and drug administration of Thailand (Thai FDA) guidance on review and approval of medicinal
products via e-submission 2023
https://drug.fda.moph.go.th/media.php?id=526421589043060736&name=179%20FDA-
20230623.pdf

56. Food and drug administration of Thailand (Thai FDA) guideline of product license renewal 2023
https://drug.fda.moph.go.th/announcement-administration/fda-202/

57. Act of Narcotic drug and psychotropic substances , Thailand

https://www.ratchakitcha.soc.go.th/DATA/PDF/2564/A/073/T_0001.PDF

108
58. Food and drug administration of Thailand (Thai FDA) guidance on safety reporting of narcotic drug
and psychotropic substances 2015 https://hpvcth.fda.moph.go.th/category/ae-
reporting/guidelines-for-licensees-to-report-safety/

59. National Pharmaceutical Regulatory Agency (NPRA),Ministry of Health Malaysia, Malaysian

Guidelines on Good Pharmacovigilance Practices (GVP) for Product Registration Holders 2021
https://npra.gov.my/easyarticles/images/users/1047/Malaysian-Guidelines-on-Good-
Pharmacovigilance-Practices-GVP-For-Product-Registration-Holders-First-Edition-August-2021.pdf

60. National Pharmaceutical Regulatory Agency (NPRA),Ministry of Health Malaysia, Malaysian guidance
document on voluntary good pharmacovigilance practices (GVP) inspection 2022
https://www.npra.gov.my/easyarticles/images/shared/FV/Guidelines/Finalised-Guidance-
Document-on-Voluntary-GVPI-14032022.pdf

61. Health science authority (HSA), Singapore guidance for industry; post-marketing vigilance
requirements for therapeutic products and cell, tissue and gene therapy products 2021
https://www.hsa.gov.sg/docs/default-source/hprg-vcb/guidance-document/guidance-for-industry--
post-marketing-vigilance-requirements-for-therapeutic-products-and-cell-tissue-and-gene-therapy-
products_v3_01mar2021.pdf

62. Pharmacovigilance activities in JAPAN https://www.pmda.go.jp/files/000164763.pdf

63. International Organization for Standardization (ISO); www.iso.org
64. Sawyer LB, Dittenhofer MA. Sawyer’s Internal Auditing. 5th ed. Altamonte Springs, FL: The IIA
Research Foundation; 2003
65. Strengthening Collaboration for Operating Pharmacovigilance in Europe Joint Action (SCOPE JA);
www.scopejointaction.eu.
66. European Union Commission Implementing Regulation on the Performance of Pharmacovigilance
Activities Provided for in Regulation (EC) No 726/2004 and Directive 2001/83/EC https://eur-
lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2012:159:0005:0025:EN:PDF
67. Therapeutic Goods Administration (TGA) , Australia-specific annex to the EU RMP, Australian
requirements and recommendations 2019.
https://www.tga.gov.au/resources/resource/guidance/risk-management-plans-medicines-and-
biologicals/australia-specific-annex-eu-rmp
68. Therapeutic Goods Administration (TGA) , Risk Management Plan for medicines & biologics,
Australian requirements and recommendations 2019
https://www.tga.gov.au/resources/resource/guidance/risk-management-plans-medicines-and-
biologicals

109
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