Pharmacovigilance Study Material (Download).pdf

Accredited & Certified Institution
Pharmacovigilance

Introduction to:
Pharmacovigilance,
History and
Development of
Pharmacovigilance

Pharmacovigilance
History Of PV
Rationale for PV
Why Pharmacovigilance is
needed in every country?
Introduction to PV
guidelines
Challenges in PV
Sources of PV
1.
2.
3.
4.
5.
6.
7.
Contents

Pharmacovigilance
The word Pharmacovigilance can be divided into
‘Pharmakon’ and ‘Vigilance’.
In Greek Pharmakon means ‘a drug or medicine’ and the
word ‘Vigilance’ has been derived from a Latin word
‘Vigilare’, which means ‘to watch’.
Pharmacovigilance is the science and activities relating
to the detection, assessment, understanding and
prevention of adverse effects or any other possible drug-
related problems. (As per WHO guidelines)
Scope of Pharmacovigilance
Drugs
Herbals
Traditional and complementary medicines
Blood products
Biologicals
Medical devices
History of PV

History of PV contd..
Thalidomide Tragedy (1961)

Why Pharmacovigilance is needed in every
country?
There are differences between countries in the occurrence
of adverse drug reactions because of differences in:
Genetics, diet, traditions of the people
Drug production
Distribution and use (e.g. indications, dose, availability)
Pharmaceutical quality and composition (excipient) of
locally produced pharmaceutical products
The use of non-orthodox drugs (e.g. herbal remedies)
which may pose special toxicological problems, when
used alone or in combination with other drugs.
Who can Report?
Adverse
events
Physicians
Nurses
Pharmacists
Drug
manufacturers
Lawyers
Patients

How to Report?
Adverse reactions can be reported directly to regulatory
authorities or marketing authorization holder or national
pharmacovigilance centers or local drug safety centers
through either:
Calls
Emails
Fax
Online Reporting via MedWatch or Yellow Card
Challenges in PV
Lack of harmonization
Diverse culture and different languages
PV is not seen as a priority in some Asian countries
Lack of human and financial resources with experian the
regulatory agencies
Lack of budget and government support
Lack of awareness on PV amongst physicians and
public.
Underreporting and poor quality of spontaneous reports
PV Guidelines
ICH PV Guidelines
ICH E2A Clinical Safety Data Management: (Definitions
and Standards for Expedited Reporting)
ICH E2B Data Elements for Transmission of Individual
Case Safety Reports (Both the Revisions (R2) as well as
R3 are currently active)

PV Guidelines contd..
ICH E2C (R2) Periodic Benefit risk evaluation report (PBRER)
ICH E2D Post approval Safety Data Management:
Definitions and Standards for Expedited Reporting
ICH E2E Pharmacovigilance Planning
ICH E2F DSURs
ICH M1 Medical Terminology- MedDRA
ICH M2 Electronic standards for Transmission of
Regulatory Information (ESTRI) - ICSR
Country specific PV Guidelines
GVP module for Europe
21 CFR for FDA
Process of PV
Individual Case
Safety Reports
(ICSRs)
Aggregate
Reporting
Signal Detection Risk Management
• Serious and
unexpected
AEs are subject
to expedited
reporting
To review the
cumulative
safety
information
from a wide
range of
sources, on a
periodic basis
and submit to
regulators
worldwide.
Process of
determining
AEs associated
with particular
drugs and
comparing the
same to that
for other
similar drugs.
Assessing the
Risk-Benefit
profile of the
Drug

Aggregate Reporting
Aggregate Reporting is the process that reviews the
cumulative safety information from a wide range of sources,
on a periodic basis and submit the findings to regulators
worldwide.
The aggregate safety reports are submitted to regulators for
as long as the medicine is marketed anywhere in the world
and enables understanding of risk benefit profile of product
over a period of time.
Example of Aggregate Reporting
Pre-marketing Reports
NDA Annual Reports
IND annual reports
Clinical Study Reports (CSR)
Post-marketing Reports
Periodic Safety Update Report (PSUR)
Periodic Benefit Risk Evaluation Report (PBRER)
Periodic Adverse Drug Experiences Reports (PADER)
Summary Bridging Report (SBR)
Development Safety Update Report (DSUR)
Annual Safety Reports (ASR)
Signal Detection
As per CIOMS, Signal a information that arises from
one or multiple sources, which suggests

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
actions.
Risk Management
A set of pharmacovigilance activities and interventions
designed to identify, characterize and prevent or minimize
risks relating to medicinal products, including risk
communication, and the assessment of the effectiveness of
risk-minimization interventions.
Purpose:
Identify the risks associated with a medicinal product
Develop methods to clarify further the safety profile of a
product
Plan ways to minimize risk to individual patients
Remember: Every minute spent on reporting improves the
quality of life of your patients

Pharmacovigilance Overview
Objective
What is pharmacovigilance
Pharmacovigilance center in India
History of Pharmacovigilance
Who reports
What to report
How it is categorized
Reporting methods
Reporting timings
Flow of data
Methods to assessment( scales/ algorithms)
Data mining/ software used
MedDRA
Discussion,
conclusion
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
World Health Organization
The science and activities relating to the detection,
assessment, understanding and prevention of adverse effects
or any other drug-related problem

Drug ADR Company Year
Rofecoxib
Myocardial
infarction
Merck 2004
Cerivastatin Rhabdomyolysis Bayer 2001
Cisapride Cardiac arrythmia J&J 2000
Astemizole Cardiac arrythmia J&J 1999
Bromfenac Liver toxicity Wyeth 1998
Why pharmacovigilance?
Humanitarian concerns
Hippocrates’ admonition.
“First, do no harm”
Check if drugs on the market fulfill their intended role in
society i.e. if resources spent on drugs produce optimal
results in terms of benefits.
Drugs withdrawn from Market due to
severe ADR

WHO ALL ARE INVOLVED
Consumer
Doctor/ dentist/ health professional
Social service personal
Drug company
Veteran
Animal owner
Regulatory authorities
The problem of ADRs
Account for 5% of all hospital admissions.
Occur in 10-20% of hospital inpatients.
Cause death in 0.1% of medical and 0.01% of surgical
inpatients.
Adversely effect patients quality of life.
Cause patients to lose confidence in their doctors.
Increase costs of patients care.

What to report: ADVERSE EVENT-1
Any unfavourable, unintended sign, symptom, illness or
experience (untoward medical occurrence) that
develops or worsens in a subject during the period of
observation (defined by protocol) « Adverse event »
does not imply causal relationship with the study
medication
Abnormal results of diagnostic procedures, including
laboratory findings considered by investigator to be of
clinical relevance, are considered to be adverse events
ADVERSE DRUG REACTION
“A noxious and unintended
response at doses normally
used for prophylaxis, diagnosis,
or therapy of diseases, or for the
modification of physiological
function.”
All ADRs are AEs…….
but all AEs are NOT ADRs

SAE
results in death
is life threatening
requires inpatient hospitalisation or prolongation
of existing hospitalisation
results in persistent or significant disability/incapacity
is a congenital anomaly/birth defect
is important medical event
WHAT IS NOE/SAET AN A?
Surgical Procedures
They are therapeutic measures of a condition requiring
surgery
They are not AEs/SAEs per se;
The condition for which the surgery is performed, may be
an AE/SAE which has to be reported
Surgical procedures planned prior to randomization and
conditions leading to these measures are not adverse
events (medical history)
An Unexpected ADR
An ADR whose nature, intensity or incidence falls outside
the information provided in
the Investigator’s Brohcure
the Package Insert or Product Monograph of a marketed
drug

Complete
recovery
Ongoing
Recovered
with
sequelae
Unknown
Death
DIMENSIONS OF AN ADVERSE EVENT
Adverse Event
Intensity
Seriousness Expectedness
Relatedness
Mild
Moderate
Severe
Serious
Non
serious
Expected
Unexpect
ed
Related
Un-
related
OUTCOME OF AN AE & FOLLOW UPS
Follow Ups are necessary
to know outcome
(ongoing)
get critical missing
information
(concomitant med.)
hospital / lab reports
(autopsy report)
causal assessment
(revision / delayed)

CAUSAL ASSESSMENT – WHO ALGORITHM
Certain
Probable
Possible
Unlikely
Unclassifiable
REPORTING METHOD & SYSTEM
ADR form
Yellow Card
Medwatch
THE MINIMUM CRITERIA FOR A VALID ADR
REPORT*
Identifiable
patient
A suspect drug An adverse event
Identifiable
Reporter
ICH / CIOMS (Centre for international organization
of Medical Science) group V working recommend

ADR FORM
I. Reaction
Information
II. Suspect Drug
III. Concomitant Drugs
& History
IV. Manufacture’s
Information
LAWS, REGULATIONS AND GUIDELINES
Schedule Y requirements
ICH guidelines
International regulations (US FDA)

CURRENT US FDA REGULATIONS
Safety reporting requirements are specified in
Title 21, Code of Federal Regulations:
Part 310.305
Part 312.302
Part 314.80
Part 314.98
Part 600.80
Old Drugs (marketed pre-1938)
Safety reporting from INDs
Marketed drugs
Generic drugs
Therapeutic Biologic products

ICH-GCP GUIDELINES - III
E2A
E2B
E2B(M)
E2C & E2C
E2D
E2E
Expedited clinical safety reporting
Safety reporting data elements spec’s
Data Elements for Electronic submission
Addendum – PSURs
Post-marketing expedited reporting standard
Pharmacovigilance planning
The post marketing surveillance may
comprise of one of the following;
Phase IV
Clinical
Trials
PMS
Studies
Observa
tional
Studies
Registries
Prescript
ion
Event
Monitori
ng
Spontan
eous
reporting

AIMS OF POST MARKETING SURVEILLANCE
Expose more patients to confirm and better understand
safety of new molecule (delayed effects, prolonged use
effects.
Evaluation in unexposed population (children, pregnant
women, nursing mothers, elderly, immuno-suppressed)
Identification of risk groups
Occurrence of rare and serious ADRs
Assessment of costs of ADRs to various sectors of the society
SPONTANEOUS REPORT
“An unsolicited communication to a company, regulatory
authority or other organization that describes an adverse drug
reaction in a patient given one or more medicinal products and
which does not derive from a study or any organized data
collection scheme is called “Spontaneous Report”.
Strengths Weaknesses
Cornerstone of ‘PV’
Cheap & Easy
Encompass all clinical
settings
Life-time span
Detection of rare ADRs
Underreporting
Quality of reporting
No denominator
Subject to bias
Delayed effects go
undetected

PSUR- PERIODIC SAFETY UPDATE REPORTS
Its a formal, structured update of the worldwide safety
experience for a registered medicinal product (per ICH E2C
standards), prepared for submission to regulatory
authorities at defined times post-authorization
PERIODIC SAFETY UPDATE REPORTS
New safety information from appropriate sources.
Data to patient exposure.
Summarizes the market authorization status in different
countries.
Create periodically the opportunity for an overall
safety re-evaluation.
Indicate whether changes should be made to product
information.
REPORTING TIMINGS
Schedule Y (Indian) EU Requirements US Requirements
Only ‘New Drug’
Six Monthly – first 2
years
Annual – subsequent
2 years
To be submitted
within 30 calendar
days
Even if not marketed
Six Monthly – first 2
years
Annual –
subsequent 2 years
At the first renewal,
and then
5-yearly at renewal
thereafter
One PSUR for each
active substance
To be submitted
within 60 days of last
data lock
Pre-Approval PSUR – 4
months after
application
Post Approval for each
approved
NDA/ANDA/BLA
Quarterly– for first 3
years
Then annual interval /
on request
Within 30 days of the
close of quarter
Annual reports within
60 days

THE FLOW
PV SOFT WARES & DATABASE
ArgusAERS (US FDA)
Eudravigilance (EMEA)
ARIS global
Clint race
Oracle

Med DRA: medical Dictionary for Regulatory Activities
MedDRA
MedDRA is a clinically-validated international medical
terminology used by regulatory authorities and the regulated
biopharmaceutical industry.
The terminology is used through the entire regulatory
process, from pre-marketing to post-marketing, and for data
entry, retrieval, evaluation, and presentation.”
Adverse event
Medical history
Procedures
Medication
Indication

MedDRA - Structure
SOC – System Organ class
HLGT – High Level Group Term
HLT – High Level Term
PT – Preferred Term
LLT -
Low Level
Term
The Gains from PV Database
Patient’s safety & care
Dissemination of information to all concerned
Regulatory compliance
Detection of new safety issues
Changes in design / documents
Ongoing safety review
Regulatory actions

NARANJO's ALGORITHM

NARANJO's ALGORITHM
SCORING FOR NARANJO's
ALGORITHM
> 9 = definite ADR
5-8 = probable ADR
1-4 = possible ADR
0 = doubtful ADR

Three broad categories
Other methods
Irey’s method
Karch and Lasanga’s Method
Blanc et al’s method
Kramer et al’s method
FDA(Jones Method)
Emmanuel and Sacchetti’s method
The French Method
Stephen’s personal scoring method
Venulet et al’s method
Spanish quantitative imputation scale
Methods of assessment
Expert judgment/
global introspection
Algorithms
Probabilistic methods
(Bayesian approaches)

Methods of assessment
Expert judgments(global introspection):
They are individual assessments based on previous
knowledge and experience in the field.
Algorithms :
Are sets of specific questions with associated scores for
calculating the likelihood of a cause-effect relationship.
Bayesian approaches:
use specific findings in a case to transform the prior
estimate of probability into a posterior estimate of
probability of drug causation
Desirable Attributes
Reproducibility
Validity
simplicity

Drawbacks
Different causality categories are adopted in each
method, and the categories are assessed using
different criteria.
Not entirely devoid of individual judgments, so inter-
rater reliability can be low.
Which method to use?
Widely used
Naranjo WHO
WHO vs Naranjo
A disagreement
in causality
assessment
was
found in 31%
cases
Mean time
taken:
WHO
5.3±0.37
minutes vs.
Naranjo
13.26±1.33
minutes
WHO: simple
and
less time
consuming

Adverse Event and Adverse drug Reaction
An adverse drug reaction (ADR) is an unwanted or harmful
reaction experienced following the administration of a drug
or combination of drugs under normal conditions of use
and is suspected to be related to the drug.
e.g. patient experiencing anaphylaxis shortly after taking a
drug.
adverse drug reaction
adverse event
Adverse event is any undesirable event experienced by a
patient while taking a drug, regardless of whether the drug
is suspected to be related to the event e.g. patient having a
road traffic accident while on a specific medication.
Adverse event/adverse experience
Medical occurrence that may present during treatment with
a pharmaceutical product but which does not necessarily
have a causal relationship with this treatment
Classification of ADRs
Type A
Type B
Type C
Type D
Type E
Type F
Type G

Classification of adverse events
Type A
Type C
Type B
Type A effects (drug actions)
Drug interactions - may be classified as Type A effects,
although they are restricted to a defined sub-population of
patients, i.e. those taking interacting drugs.
Pharmacolo
gical
effects,
Dose related
and may often
be avoided by
using doses
which are
appropriate to
the individual
patient.
Can be
Reproduced
and studied
experimentally
and are often
already
identified before
marketing.

Type B effects (patient reactions)
Occur in only a minority of
predisposed, intolerant
patients,
Little or no dose relationship,
Generally rare and
unpredictable,
Sometimes serious,
Difficult to study .
Examples of Type B effects
Drug intolerance:
Toxic reactions, not related to overdose or diminished
elimination.
idiosyncDrugrasy:
Genetically determined abnormal reaction to the drug.
Drug allergy:
Immunologically meditated reaction that is
characterized by specificity, involvement of antibodies
or lymphocytes.
Pseudo allergic reactions:
The same clinical symptoms as allergic reaction but
without immunological specificity .

Type C effects
Use of a drug increases the frequency of a ‘spontaneous’
disease,
May be both serious and common diseases.
Often relate to long term effects.
There is often no suggestive time relationship and the
connection may be very difficult to prove.
Examples of ADRs
Common and well established ADRs
Constipation with opioids
Abdominal pain and diarrhea with erythromycin therapy.
Nausea when starting fluoxetine
Gastrointestinal symptoms with NSAIDs
Uncommon but well recognized ADRs
Achilles tendonitis caused by quinolone antibiotics
Visual field defects with vigabatrin
Uncommon emerging ADRs
Depression with rimonabant
AF with bisphosphonates
Hepatoxicity with lumiracoxib
ADRs importantance
Major clinical problem – increase morbidity and mortality.
ADRs are related to 6.5% hospital admissions in adults,
and 2.1% in children 2
6.7% hospitalized patients suffer serious ADRs 1
0.15% of hospital patients suffer fatal ADRs (= 5700 deaths
per year) 1,2
ADRS are 4th leading cause of death in the USA 1

Who might get an ADR?
Anyone who takes a medicine!
Differential diagnosis should include the possibility of an
ADR if the patient is taking any form of medication
Who is most at risk from ADRs?
The elderly
Children
Co-existing diseases
Females
Atopic individuals
Polypharmacy
50% of patients on 5drugs or more
ADRs are an increasing public health problem
Factors
elderly population
Polypharmacy
availability of OTC medicines
use of herbal/traditional medicines
medicines available via the internet
elderly population
Are ADRs avoidable?
70% ADRs are potentially avoidable
More rational Prescribing
Avoid unnecessary drug use
Dose optimization identify drugs known to produce
dose-related side effects

Consider risk factors for ADRs
Polypharmacy
Age extremes
Reduced hepatic and renal function
Patient counseling re ADR’s
Better monitoring of treatment
Better communication
What should raise your suspicion?
Timing with drug treatment.
Abnormal clinical measurements while on drug therapy
e.g. B.P, temp, pulse, blood glucose and weight
Abnormal laboratory results while on drug therapy.
Could be biochemical or hematological
New therapy started which could be used to treat ADR
Patient risk factors
Listen to patients' own concerns
Assessing causality
Nature of the reaction
Timing
Relationship to dose
Other possible causes for the symptoms
Improvement when drug(s) stopped
Has reaction been reported before
Dechallenge/Rechallenge

How common are ADRs?
Drugs most commonly implicated include NSAID, aspirin,
diuretics and warfarin
Aspirin was most frequent cause for admission
18% ADR related admissions
162 (74%) patients on aspirin 75mg OD
157 (72%) gastro-intestinal bleeding
In the UK Non Steroidal Anti-Inflammatory Drug (NSAID)
use alone accounts for3
65,000 emergency admissions/year
12,000 ulcer bleeding episodes/year

Introduction Reference Safety Information
and its Types
What is Drug Labelling?
Contents
Reference Safety Information
Company Core Data Sheet
Company Core Safety Information
Reference safety information
Investigator’s Brochure
Summary of Product Characteristics
United States Package Insert
What is Drug Labelling?
Drug labeling refers to all the printed information that
accompanies a drug including the label, the wrapping
and the packing insert.
Labeling refers to information on the labeling or outer
packaging (as per directive 2001/83/EC Art 1 (2)).
Labeling applies to prescription drugs, over-the-
counter (nonprescription) drugs and dietary
supplements.
Unexpected adverse event
Any adverse event occurring in one or more subjects
participating in a research protocol, the nature, severity,
or frequency of which is not consistent with either the
known or foreseeable risk of adverse events associated
with the procedures involved in the research that are
described in

Protocol-related documents, such as the IRB-approved
research protocol, any applicable investigator brochure,
and the current IRB-approved informed consent
document, and Other relevant sources of information,
such as product labelling and package inserts; or
The expected natural progression of any underlying
disease, disorder, or condition of the subject(s)
experiencing the adverse event and the subject’s
predisposing risk factor profile for the adverse event.
Reference Safety Information
RSI contains all relevant safety information, prepared by
the MAH and which the MAH requires to be listed in all
countries where it markets the product, except when the
local regulatory authority specifically requires a
modification.
Reference safety information is applicable at the start of
reporting periods and to be attached in appendix.
RSI also serves as reference during reporting period.
The reference product information document should list
all approved indications in ICH countries or regions in
order to facilitate the assessment of benefit and
benefit-risk by indication.
The reference product information for the PBRER would
include “core safety” and “approved indications”
components.

Types of RSI
Company Core Data Sheet (CCDS)
Company Core Safety Information
(CCSI)
Investigator’s Brochures
Abbreviated prescribing information
Summary of Product Characteristics
(SPC)
Patient information leaflet (PIL)
United States Package Insert (USPI)
Japan Package Insert (JPI)
Not Mandatory: MAHs
may define core
information to aid
management of
portfolios that span
multiple territories
Mandatory:
Part of the
Marketing
Authorization
Company Core Data Sheet (CCDS)
For medicinal products, a document prepared by
marketing authorization holder (MAH) containing, in
addition to safety information, material related to,
Indications
Dosing
Pharmacology and
Other information concerning the product.
It is the reference information by which expected and
unexpected are determined for expedited reporting.
Company Core Safety Information (CCSI)
For medicinal products, all relevant safety information
contained in the company core data sheet prepared by
the MAH and which the MAH requires to be listed in all
countries where the company markets the product,
except when the local regulatory authority specifically
requires a modification.

It is the reference information by which listed and
unlisted are determined for the purposes of periodic
reporting for marketed products.
Contents of CDS/CCSI
Investigator’s Brochure (IB)
A compilation of the clinical and non-clinical data on
the investigational product which is relevant to the
study of investigation products in human subjects.
Events would be again considered as expected and
unexpected.
Contents of IB (Example)
Summary
Introduction
Physical, Chemical, and Pharmaceutical Properties and
Formulation
Nonclinical Studies
Nonclinical Pharmacology
Pharmacokinetics and Product Metabolism in
Animals
Toxicology
1.
2.
3.

Effects in Humans
Pharmacokinetics and Product Metabolism in
Humans
Safety and Efficacy
Marketing Experience
1.
2.
3.
Summary of Data and Guidance for the Investigator.
Summary of Product Characteristics
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 which
includes the information described in Article 11 of Directive
2001/83/EC.
Patient Information Leaflet (PIL)
PIL is patient friendly version of SPC.Also called as,
Package Leaflet
Package Insert
United States Package Insert (USPI)
Labeling document prepared in accordance with US
FDA’s guidelines is called United States Package Insert
(USPI).

On January 24, 2006, FDA published a final rule that
amended the requirements for the content and format
of labeling for human prescription drug and biological
products, commonly referred to as the Physician
Labeling Rule (PLR) because it addresses prescription
drug labeling that is used by prescribers and other
health care practitioners.
USPI Format
Medication Guide
Patient friendly version of USPI.
Paper based guide for patients.
Required when FDA determines
Certain information is necessary to prevent adverse
effects.

Patient should be informed about a serious side effect.
Patient adherence to directions are essential to
effectiveness.
The MAH should continuously evaluate whether any
revision of the RSI is needed whenever new safety
information is obtained throughout the reporting
interval.
Significant changes to the reference product
information made during the interval include:
changes to contraindications,
warnings/precautions sections of the RSI;
addition of ADR(s) and interactions;
addition of important new information on use in
overdose; and
removal of an indication or other restrictions for
safety or lack of efficacy reasons.
1.
2.
3.
4.
Note
When there is no CCDS or CCSI for a product, the MAH
should clearly specify the reference information being used
which may comprise national or regional product
information such as
US Package Insert (USPI)
European Summary of Product Characteristics
(SmPC)
Japanese package insert
Or local product labeling

Criteria for Expectedness
The terminologies associated with the expectedness
depend on the relevant reference safety information
(RSI):
Listed or unlisted refers to the ADR’s contained with
company core safety information data sheet (CCSI) for
a marketed product, or with in the development core
safety information (DCSI) in an investigator brochure
(IB).
Labeled or Unlabeled should only be used in connection
with official product safety information for a marketed
products such as (e.g.: summary of product
characteristics [SPC] in EU or USPI in US etc.…)

CAUSALITY ASSESSMENT OF SUSPECTED
ADVERSE DRUG REACTION
INTRODUCTION
Causality assessment – part of the 1st step in case
assessment and is based on a general system that is
intended for all reactions and all drug.
What it can do?
Decrease disagreement between accessor
Classify uncertainty
Mark individual case reports
Improve the scientific basis of assessment
What it cannot do?
Give and accurate quantitative measurement of the
likelihood of a relationship.
Distinguish valid form invalid cases
Quantify the contribution of a drug to the development
of an adverse event
Change uncertainty to certainty
The literature
Probability calculation
Aetiological – Diagnostic Systems
French imputation systems
The European ABO Systems

The US Reasonable Possibility Systems
The Naranjo ADR Probability Scale
WHO Causality Categories
The Naranjo ADR Probability Scale
The Naranjo Probability Scale
> 8 = Highly probable
5-8 = probable
1-4 = possible
0 = doubtful
C1 – Certain
C2 – Probable
C3 – Possible
C4 – Unlikely
C5 – Unclassifiable

How to assess causality
Assessing the strength of the relationship between the
drug and the event.
Can seldom say without any doubt that a specific drug
caused a specific reaction
Use the accumulation of case reports at national level is
immensely valuable providing the means for determining
real cause and effect.
Use epidemiological studies to confirm causality

Definitions
Dechallenge – withdrawing the drug(s) and recording
the outcome – improved or not improved
Rechallenge – giving one drug again under the same
conditions as before and recording the outcome –
recurrence or no recurrence.

Seriousness, Expectedness, and
Causality
The drug safety staff involved in individual case evaluation
generally have to make several decisions regarding each
case. These decisions must be made rapidly on receipt of an
individual case safety report because this determines how
the case is handled in the drug safety department and
whether, how, and when it is reported to health agencies and
business partners.
Seriousness
The generally accepted definition of seriousness is as follows:
A serious adverse event (experience) or serious adverse
reaction is any untoward medical occurrence that at any
dose:
■ results in death,
■ is life-threatening,
(NOTE: The term “life-threatening” in the definition of “serious”
refers to an event in which the patient was at risk of death at
the time of the event; it does not refer to an event that
hypothetically might have caused death if it were more
severe.)
■ requires inpatient hospitalization or prolongation of existing
hospitalization,
■ results in persistent or significant disability/incapacity, or
■ is a congenital anomaly/birth defect.

Medical and scientific judgment should be exercised in
deciding whether expedited reporting is appropriate in
other situations, such as important medical events that
may not be immediately life-threatening or result in death
or hospitalization but may jeopardize the patient or may
require intervention to prevent one of the other outcomes
listed in the previous definition. These should also usually
be considered serious.
“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 drug dependency or
drug abuse” (ICH E2A).
The European Union also notes that any suspected
transmission via a medicinal product of an infectious agent
is also considered serious
Note that the FDA slightly altered the definition of “Serious”
effective March 2011 for clinical trials by adding the concept
of “disability” directly into the definition, including the
phrase: “substantial disruption of the ability to conduct
normal life functions”.
Over the years, these definitions have been discussed,
parsed, and clarified by health agencies, companies, and
other interested observers. In general, the most
conservative interpretation is the one drug safety groups
should use. Some comments follow:

■ Death: Although one would believe this binary concept
(alive–dead) would be rather straightforward, there have
been some discussions relating to the timing of the death
and the circumstances
around the AE and the death.
■ It is fairly clear that if a patient has a myocardial
infarction (the SAE) and then over the next several hours or
days goes into shock, has severe arrhythmias, and dies,
this death is related to the SAE and this is a “fatal
myocardial infarction.” It gets trickier, however, if the
patient has a myocardial infarction and during a cardiac
catheterization goes into an intractable ventricular
arrhythmia and dies. Is the myocardial infarction to be
classified as a fatal one or is the death a sequelum of the
catheterization? There is no clear answer, and it may vary
from case to case. The most conservative call is often
used by drug safety units; that is, the death is a part of (or
consequence of) the SAE. However, if a medically
defensible call is made that is less conservative, this should
be noted somewhere in the case along with the reasoning
behind this decision.
Another example would be that of a fall. If a patient trips
while walking on a level surface, falls, and scrapes his or
her knee, this is most probably a nonserious AE. If, however,
he or she falls while standing on a ledge or walking down a
staircase and dies as a result of the fall, the case should be
reported as a serious and fatal case but how to classify it is
tricky. The fall may be nonserious, but the sum of the case
is clearly serious and fatal because of the fatality occurring
after the fall, not the actual fall. s due to the

circumstances of standing near the ledge. Had the fall
occurred on the level surface none of the events leading to
the death would have occurred.
■ In a 1996 report on a survey done at the United States and
European Union Drug Information Association meetings in
1993, Dr. Win Castle and Dr. George Phillips reported marked
transatlantic differences in the interpretation of seriousness
and expectedness. For example, “total blindness for 30
minutes” was believed to be serious by 89% in the European
Union survey and 44% in the United States survey compared
with “mild anaphylaxis,” which was believed to be serious by
37% of the EuropeanUnion responders and 98% of the United
States responders. Whether this is still the case remains to be
seen, but the results nonetheless are most interesting and
suggest the need for harmonization and training of safety
reviewers (Castle, Phillips, Standardizing “expectedness” and
“seriousness” for adverse experience case reporting.
Drug Inform J 1996;30:73–81).
Life-threatening: This concept also has interpretation issues
revolving around whether the SAE would truly kill the patient if
untreated. A mild myocardial infarction with no cardiac
function compromise or arrhythmias might be considered
serious (medically significant if not hospitalized) but not life-
threatening, whereas a myocardial infarction that progresses
over the next hour or two to pulmonary edema would be
considered life-threatening. This definition thus may overlap
to a degree with “medically significant.” Again, most would
take a conservative approach. Note that FDA changed the
definition effective March 2011 to include the requirement that
the idea of whether an AE is life-threatening should be
commented upon by both the investigator and the sponsor
and that if either one feels it is, then the AE should be so
considered

■ Hospitalization: Much debate occurred over what
actually constitutes “hospitalization” or “inpatient
hospitalization.” Some patients may be kept overnight
(even up to 24–36 hours) in the emergency department for
observation and treatment but not “formally” admitted to
the hospital as an inpatient. Thus, this patient would not
qualify as serious based on a stay in the emergency room
(see the Food and Drug Administration’s 2001 draft
guidance on AE reporting, Section IV.A.3. Web Resource 13-
1). In the European Union Directive 2001/83/EC and Volume
9A, refer to the definition of serious adverse reaction,
including “inpatient” hospitalization.
■ Significant or persistent disability/incapacity: A relatively
uncommon criterion in practice. Not formally defined. The
FDA gives an interesting example in its 2001 draft .
Persons incarcerated because of actions allegedly caused
by a drug (e.g., psychotropic drugs and rage reactions)
have sustained a substantial disruption in their ability to
conduct normal life functions. Thus, these adverse
experiences would qualify for a significant or persistent
disability/incapacity outcome. Note the change referred to
earlier in this chapter about the FDA’s addition of this
concept directly into the definition of “serious.”
■ Congenital anomaly/birth defect: Usually rather
straightforward. It would include even mild birth defects.
The FDA also notes that this includes those defects
“occurring in a fetus,” thus covering abnormalities
discovered before birth.

■ Important medical events (also called “significant
medical events”): This criterion has often been difficult to
handle for pharmacovigilance departments because the
definition relies on medical judgment. The examples are
given (allergic bronchospasm, blood dyscrasias, or
convulsions) do not necessarily help to clarify other less
dramatic situations. The FDA also gives examples of drug
dependency or drug abuse as important events.
Often, cases elicit hours of debate in drug safety units on
whether to consider them medically important. Is a mild
focal seizure medically important? Is a platelet count 10%
below the lower level of normal medically important? Other
examples abound. Various rules of thumb have developed:
■ If it happened to you or a family member, would you
consider it important or medically significant?
■ If you discuss or debate whether a case is medically
important, it is.
■ Another method involves using the FDA’s “always
expedited” list (see Chapter 8) as published in “the Tome”
(see Chapter 4) or the equivalent lists from other health
authorities
If a member of the marketing or sales department or a
nonmedical professional believes it is not important, it is
important. (This “rule,” though some what jocular and
cynical, has developed to note the real observation that
sometimes there are nonmedical pressures put on
personnel in the safety department to interpret cases or
make decisions based on sales, financial, or other
nonmedical criteria.

This is an unfortunate fact of life—not just in the
pharmaceutical world but in the world of clinical medicine,
where many judgments are now made on a cost-
effectiveness basis. Always keep in mind that the primary
mission of the drug safety department is to protect the
public health.)
Expectedness
The United States regulations governing expectedness are
fairly straightforward:
or a pre-marketed product: Any adverse drug experience,
the specificity or severity of which is not consistent with the
current investigator’s brochure; or, if an investigator
brochure is not required or available, the specificity or
severity of which is not consistent with the risk information
described in the general investigational plan or elsewhere
in the current application, as amended. For example, under
this definition, cerebral thromboembolism and cerebral
vasculitis would be unexpected (by virtue of greater
specificity) if the investigator brochure only listed cerebral
vascular accidents (21CFR312.32(a)). FDA added to this
definition effective March 2011 by noting in 21CFR312 that
“Unexpected, as used in this definition, also refers to
adverse events or suspected adverse reactions that are
mentioned in the investigator brochure as occurring with a
class of drugs or as anticipated from the pharmacological
properties of the drug, but are not specifically mentioned
as occurring with the particular drug under investigation.”
That is, an AE in the class labeling section of the brochure
without a specific mention of the study drug is considered
unexpected.

For marketed products: Any adverse drug experience that is
not listed in the current labeling (package insert or
summary of product characteristics) for the drug product.
This includes events that may be symptomatically and
pathophysiologically related to an event listed in the
labeling, but differ from the event because of greater
severity or specificity. For example, under this definition,
hepatic necrosis would be unexpected (by virtue of greater
severity) if the labeling only referred to elevated hepatic
enzymes or hepatitis.AEs that are “class-related” (i.e.
allegedly seen with all products in this class of drugs) which
are mentioned in the labeling (package insert or summary
of product characteristics) or investigator brochure but
which are not specifically described as occurring with this
product are considered unexpected” (21CFR314.80(a))
In the European Union, expectedness is addressed in
Directive 2001/20/EC, which simply notes that an
unexpected reaction is one “the nature or severity of which
is not consistent with the applicable product information
(e.g. investigator’s brochure for an unauthorized
investigational product or summary of product
characteristics for an authorised product).”
In theory, this concept is rather straightforward, but in
practice, it becomes somewhat harder when synonyms
and overlapping concepts are considered. In the report
cited previously by Castle and Phillips, 72% of the European
Union responders believed that if the labeled event is
“dizziness,” then “vertigo” would also be considered
expected (labeled), but only 50% of the United States
responders believed vertigo was labeled. Similarly, 18% of
the European Union responders and 3% of the

United States responders believed that if “hypotension,
wheezing, and urticaria” are labeled, then a reported term
of anaphylaxis would also be expected. Whether these
differences persist, many years after the survey is unclear.
However, it does highlight the fact that well-trained
experienced medical personnel doing pharmacovigilance
can take the same set of facts and come up with differing
and even opposing views
In general, one should decide expectedness without
thought to seriousness. That is, just because a case is
nonserious and the AE in question is mildly severe and of
little medical import (e.g., a maculopapular rash)
compared with a serious AE (e.g., severe hepatitis), the
decision on expectedness should be made purely on the
basis of the wording in the label and not on the seriousness.
Give each AE its due.
With clinical trial drugs, especially those not yet marketed,
there may be minimal or no human experience (e.g., the
first study in humans or the first phase II study after phase I
studies that showed no AEs). In this case, there are no
labeled events in the investigator brochure, and everything
is thus “new” and unexpected. Anticipated events based on
the pharmacologic properties of the drug should not be
considered expected until actually reported in a patient
and put into the brochure.
In some cases, it is necessary to consider the route of
administration, dosage, or indication being studied when
assessing the expectedness. This usually depends on how
the investigator brochure or marketed labeling is written.
Some describe a different set of AEs for different indications,

dosages, or routes of administration. Care must be taken to
apply the correct label to each case when doing
expectedness
The general advice would be, as with seriousness, to decide
on the side of conservatism. Then, if there are questions on
whether an AE is expected, consider it unexpected.
Relatedness(Causality)
Of the three criteria revolving around the regulatory
reportability of an individual case (seriousness,
expectedness, and relatedness), this one is often the most
difficult to do for the multiple reasons explained next.
Causality may be determined initially at the individual case
level, after the receipt of an individual case safety report
and again after the review of aggregate data in a case
series as for signaling, risk management, and various
regulatory reports, such as PSURs.
First, some basic “housekeeping” points should be cleared
up to ensure that cases are always handled and collected
in the same manner. In doing case assessments, one
should be sure that cases are coded using the same
MedDRA version and codes (some older dictionaries may
still be used and some labeling for older drugs may not be
in MedDRA), with trained coders who use the consistent
methodology and synonym lists. For aggregate reports, the
search criteria for the case series should be complete and
standardized (using searches from the MSSO and/or
CIOMS). Where possible, Standardized MedDRA Queries
(SMQs) should be used. See Web Resource 13-2. See
Chapter 14 on coding. Cases should be followed up (rapidly
upon receipt, not at a later date) as appropriate to ensure
the maximum amount of high-quality data.

In practice, many companies have two sets of standards
and classifications for causality assessment of individual
case safety reports. The first is used in clinical trials by the
medical research group and the investigator (a separate
causality assessment for each case should be done by the
investigator and the sponsor as noted by FDA in the
updating of the clinical trial regulations effective March
2011). The second is used in the drug safety unit.
As there is no standard system, various categories (usually
three to six) are used in case reports in clinical trials as
follows:
■ Related
■ Probably related
■ Possibly related
■ Weakly related
■ Unrelated
■ Unassessable
This methodology is useful in later analyzing signals and in
creating tables for investigator brochures, product labeling,
and monographs to give a feel for the certainty or lack
thereof about the causality of AEs by the drug in question.
However, for the drug safety group, which has to determine
whether a clinical trial case meets the three criteria
(seriousness, expectedness, causality) for expedited
reporting, the decision is yes or no. That is, the drug safety
group must make the choice between unrelated and
related. There is no middle ground or gray zone for
causality here. Thus, the drug safety group has to make a
rapid decision on whether the case is clearly unrelated
(absolutely, positively) or everything else .

Effective March 2011, the FDA changed the causality
regulations, introducing the concept of “reasonable
possibility” (21CFR32): Suspected adverse reaction means
any adverse event for which there is a reasonable
possibility that the drug caused the adverse event. For the
purposes of IND safety reporting, ‘‘reasonable possibility’’
means there is evidence to suggest a causal relationship
between the drug and the adverse event. A suspected
adverse reaction implies a lesser degree of certainty about
causality than an adverse reaction, which means any
adverse event caused by a drug. This wording changes the
older concept of “possible association” to “reasonable
possibility.” It is not clear that this will make a major
difference in practice.
Methodology
Because there are no clear standards or classifications for
causality, two broad methods have been developed for
causality assessment. (Bayesian analysis is a third method,
but this has not proved practical yet.)
Global Introspection
The first is known as “global introspection,” which is a
somewhat jocular description of having one or more smart
experienced drug safety experts (usual physicians) read
the case details, in particular the narrative, and decide on
“introspective” grounds for whether the case is caused by
the drug. Obviously, all the expected difficulties exist when
the decision is left to one or more human beings using
subjective criteria: different training, different experience,
untested interrater reliability, biases, and pressure from
others within the company or institution.

A French group in a 2005 publication on causality found
that the overall agreement among five senior experienced
experts using global introspection was poor and varied
according to level of causality (Arimone, Bégaud,
Miremont-Salamé, et al., Agreement of expert judgment in
causality assessment of adverse drug reactions. Eur J Clin
Pharmacol 2005;61[3]:169–173). So, in practice, companies
try to get solid, smart, ethical individuals with thick skins
and a strong desire to protect the public health to do this
job to make the causality judgments.
These criteria are used in global introspection:
Reasons to suspect the AE was caused by the drug.
■ The AE occurred in the expected time frame (as a
function of the drug’s pharmacologic or clinical half-life).
■ No problems or symptoms before exposure.
■ No other medical conditions that could cause this AE.
■ No concomitant medications that could cause this AE.
■ A positive dechallenge and (better) a positive
rechallenge.
■ The AE is consistent with the established mechanism of
action of the product (“biologic plausibility”)
■ A known class effect.
■ Lack of alternative explanation.
■ A dose-response.
■ A “typical” adverse drug reaction (e.g., low background
rate), such as a fixed drug reaction that would not
generally be seen except when due to a drug.
■ A “clean subject” (e.g., a child).
■ Consistency of time to onset (e.g., early for
immediatehypersensitivity or long-term for
tutumorigenesis).
■ Similar findings in toxicity studies.

■ Positive in vitro test (e.g., immunoglobulin E antibodies to
allergen and elevated serum tryptase in anaphylaxis).
■ Positive in vivo test (e.g., intradermal or prick test for
immediate hypersensitivity or patch test for delayed
hypersensitivity).
■ Identified subset at risk or predisposing factor
■ Lack of protopathic bias: a drug given to treat early
symptoms may appear temporally associated with the
subsequent illness, particularly if the drug’s efficacy is low.
Algorithm
Algorithms represent the second method and the usual
alternative to global introspection. They have in general not
succeeded as well as global introspection when used alone,
though they can be useful when used in conjunction with
global introspection. Algorithms represent a decision tree
that is computerizable and allows yes/no answers to preset
questions to determine a causality result. Obviously, the
algorithm is only as good as the questions asked and the
data provided. Because of the inability to make a “one size
fits all” algorithm, there is usually a final human review to
ensure that the algorithm results are “reasonable” for the
situation. More than 30 algorithms have been developed for
both manual and computerized causality assessment of
individual cases in pharmacovigilance. One of the earlier
used algorithms was developed by Professor J. Venulet in
1980 and updated in 1986 (Venulet, Ciucci, Bernecker, Int J
Clin Pharmacol Ther Toxicol 1986;24:559).

In a study to evaluate the agreement between various
algorithms and those obtained from an expert panel using
the World Health Organization method, 200 reports were
studied. The rates of concordance between assessments
made using the algorithms and those of the expert panel
were 45% for “certain,” 61% for “probable,” 46% for “possible,”
and 17% for drug-unrelated terms. Correcting for
confounding variables did not significantly improve the
results. The authors concluded that full agreement with
global introspection was not found for any level of causality
assessment (Macedo, Marques, Ribeiro, et al., J Clin Pharm
Ther 2003;28:137)
HealthAuthorityGuidanceand Requirements
There is no international standard for causality assessment
or classification. The United States and European Union
recommendations are summarized below.
■ UnitedStatesFDA
Current United States regulations require a causality
assessment for IND expedited 7- and 15-day reports. These
regulations require an IND safety report (21CFR312):
The sponsor must notify FDA and all participating
investigators (i.e., all investigators to whom the sponsor is
providing the drug under its INDs or under any investigator’s
IND) in an IND safety report of potentially serious risks, from
clinical trials or any other source, as soon as possible, but in
no case later than 15 calendar days after the sponsor
determines that the information qualifies for reporting.... In
each IND safety report, the sponsor must identify all IND
safety reports previously submitted to FDA concerning a
similar suspected adverse reaction,

and must analyze the significance of the suspected
adverse reaction in light of previous, similar reports or any
other relevant information
An unexpected adverse event or unexpected suspected
adverse reaction is defined by FDA in the regulations as
unexpected if it is not listed in the investigator brochure or
is not listed at the specificity or severity that has been
observed; or, if an investigator brochure is not required or
available, is not consistent with the risk information
described in the general investigational plan or elsewhere
in the current application, as amended. For example, under
this definition, hepatic necrosis would be unexpected (by
virtue of greater severity) if the investigator brochure
referred only to elevated hepatic enzymes or hepatitis.
Similarly, cerebral thromboembolism and cerebral
vasculitis would be unexpected (by virtue of greater
specificity) if the investigator brochure listed only cerebral
vascular accidents. ‘‘Unexpected,’’ as used in this definition,
also refers to adverse events or suspected adverse
reactions that are mentioned in the investigator brochure
as occurring with a class of drugs or as anticipated from
the pharmacological properties of the drug, but are not
specifically mentioned as occurring with the particular
drug under investigation.
For NDA 15-day expedited reports, there is “implied”
causality for spontaneous reports. What this means is that
if a healthcare professional or consumer takes the time to
report an AE to the manufacturer of the drug or to the FDA,
the implication is that the reporter believes that to some
degree the drug may have caused the AE. This is not
clearly stated in the regulations that require 15-day
expedited reports, as follows

Postmarketing 15-day “Alert reports.” The applicant shall
report each adverse drug experience that is both serious
and unexpected, whether foreign or domestic, as soon as
possible but in no case later than 15 calendar days of initial
receipt of the information by the applicant”
In the draft “Guidance for Industry Postmarketing Safety
Reporting for Human Drug and Biological Products
Including Vaccines” of March 2001 (Web Resource 13-1), the
FDA notes the following:
For spontaneous reports, the applicant should assume that
an adverse experience or fatal outcome was suspected to
be due to the suspect drug or biological product (implied
causality). For clinical studies, an adverse experience or
fatal outcome need not be submitted to the FDA unless the
applicant concludes that there is a reasonable possibility
that the product caused the adverse experience or fatal
outcome (see §§ 310.305(c)
(1)(ii), 337314.80(e)(1), and 600.80(e)(1))
Causality Assessment—Determination of whether there is a
reasonable possibility that the product is etiologically
related to the adverse experience. Causality assessment
includes, for example, assessment of temporal
relationships, dechallenge/rechallenge information,
association with (or lack of association with) underlying
disease, presence (or absence) of a more likely cause, and
physiologic plausibility
In the draft “Guidance for Industry: Good
Pharmacovigilance Practices and Pharmacoepidemiologic
Assessment” of March 2005, at Web Resource 13-4, the FDA
notes the following:

For any individual case report, it is rarely possible to know
with a high level of certainty whether the event was caused
by the product. To date, there are no internationally
agreed-upon standards or criteria for assessing causality
in individual
cases, especially for events that often occur spontaneously
(e.g., stroke, pulmonary embolism). Rigorous
pharmacoepidemiologic studies, such as case-control
studies and cohort studies with appropriate follow-up, is
usually employed to further, examine the potential
association between a product and an adverse event
The FDA does not recommend any specific categorization
of causality, but the categories probable, possible, or
unlikely have been used. The WHO uses the following
categories: certain, probably/likely, possible, unlikely,
conditional/unclassified, and unassessable/unclassifiable.
Although the FDA does not advocate a particular
categorization system, if a causality assessment is
undertaken, the FDA suggests that the causal categories
are specified.
In contrast to causality assessment at the individual case
level, it may be possible to assess the degree of causality
between the use of a product and an AE when a sponsor or
health authority gathers and evaluates all available safety
data in aggregate, including the following:

1. Spontaneously reported and published case reports
2. Relative risks or odds ratios derived from
pharmacoepidemiologic safety studies
3. Biologic effects observed in preclinical studies and
pharmacokinetic or pharmacodynamic effects
4. Safety findings from controlled clinical trials
5. General marketing experience with similar products in
the class
FDA concludes: “After the available safety information is
presented and interpreted, it may be possible to assess the
degree of causality between the use of a product and an
adverse event.”
European Union
The European Union position on causality is explained in
ENTR/CT3, “Detailed Guidance on the Collection, Verification
and Presentation of Adverse Reaction Reports Arising from
Clinical Trials on Medicinal Products for Human Use” (April
2006). (Web Resource 13-5.)
All adverse events judged by either the investigator or the
sponsor as having a reasonable suspected causal
relationship to an investigational medicinal product qualify
as adverse reactions. The causality assessment given by
the investigator should not be downgraded by the sponsor.
If the sponsor disagrees with the investigator’s
causality assessment, both the opinion of the investigator
and the sponsor should be provided with the report.

The MHRA (United Kingdom) comments extensively on this
situation (consistent with the general European Union
position) in its publication Good Pharmacovigilance
Practice Guide (Pharmaceutical Press, London 2009,page
133):
If the investigator states that the event is not related, it is
recommended that the SAE form should prompt the
investigator to provide details.… If the investigator assigns
the causality as “not assessable,” the sponsor should adopt
a conservative approach in which the event is deemed a
suspected adverse reaction until follow-up information is
received from the investigator. This scenario also applies
should the investigator not supply a causality assessment…
the event should be considered causally related.… The
sponsor is also required to make an assessment of
causality, as he or she will have greater knowledge of the
product upon which to base the causality assessment.
For many years, the French government has used an
imputabilité decision table based on a combination of a
“bibliographic” score (from never reported to well known),
chronological criteria (timing, dechallenge, rechallenge),
and clinical criteria (specific laboratory findings, suggestive
clinical picture, other explanations likely), leading to a five-
degree global score (0, unrelated; 1, doubtful; 2, possible; 3,
probable; 4, definite) (Begaud, Drug Inform J 1984;18:275). It
is not used outside of France.

CIOMSI Assessment of Causality
It should be emphasized that manufacturers should not
separate out the spontaneous reports they receive into
those that seem to themselves to be causally related to
drug exposure and those they consider not causally
related. A physician in making a spontaneous report to a
manufacturer is indicating that the observed event may be
due to the drug, i.e. the physician suspects that the event is
a reaction. In such a case, it would be inappropriate for a
manufacturer to impute to the reporting physician an
assessment of causality. Thus all spontaneous reports of
serious unlabelled reactions made by medical
professionals should be considered as CIOMS reports.
However, submission of such a report does not necessarily
constitute an acceptance of causality by a manufacturer
Uppsala Monitoring Centre (WHO)
The Uppsala Monitoring Centre uses six categories: (1)
certain, (2) probably/likely, (3) possible, (4) unlikely, (5)
conditional/unclassified, and (6)
unassessable/unclassifiedable.They note that these
categories are the most widely used, although not
everyone uses all of them. See Web Resource 13-6.
Judgment of Cases When Received Versusat the time of
Periodic Reporting and Signaling

Most of this chapter dealt with judging cases at the time of
receipt. For causality, this is primarily for clinical trial cases.
Judgment of seriousness, expectedness, and causality in
the acute phase upon receipt is often done within
complete information and in a vacuum. At the time of
signaling or PSUR preparation, the reviewers now have the
benefit of complete (or at least more complete)
information on each case, a case series, perhaps a review
of animal and other preclinical data, a literature review,
and so on. This allows a more nuanced and reasoned
judgment. It is not uncommon for causality and the view of
the case to change entirely as more data and more cases
come in. For example, in the early first in human clinical
trials, every AE is unexpected and new. It is very hard to
judge causality. With hindsight, later on, and with more
data, the judgment may be easier. It is highly unlikely that
the first case of valvular heart disease seen with FenPhen
was felt to be due to the drugs. Only when several occurred
did this SAE appear to be linked causally to the drug (see
Chapter 53). For cases where there is a high background
incidence, assessment of causality may take years, and
major epidemiological studies to make a valid judgment.

Active
Observational
Passive
Clinical studies
Pharmaco-
vigilance
Methods
Methods in Pharmacovigilance
Drug Safety Pharmacovigilance
Types of surveillance/methods
▶ Passive surveillance
▶ Active surveillance
▶ Comparative observational studies
▶ Clinical studies
Passive surveillance
▶ Spontaneous reporting
▶ Stimulated reporting
▶ Intensified reporting
▶ Targeted spontaneous reporting

Spontaneous reporting
▶A functional ADR system to monitor the safety of all
medicines
▶ Reports are submitted voluntarily by health care
professionals, pharmaceutical companies or patients to
the pharmacovigilance centre
▶ Reporting systems are based on suspected ADRs
▶ Data are collected in a central or regional data base
▶ Reporting form contains- reporter details, patient details,
suspected product details and the description of
suspected reaction
▶ This reporting is based on suspected adverse drug
reactions
▶ Cases are not collected systematically
Pros Cons
Covers the whole population Inherent under reporting
Includes all medicines Captures only suspected ADRs
Continuous monitoring through-
out the life cycle of a medicine
Reporting bias- seriousness,
severity, publicity of specific ADRs
Signals of new, rare and
serious ADRs can be obtained
Difficult to detect-delayed ADRs
Most commonly used
pharmacovigilance method
Difficult to calculate reliable rate
and measure risk factors
Easiest method to establish
Deaths are poorly reported
Relatively Inexpensive
Limitations in special areas-
pregnancy, paediatrics

Intensified ADR reporting
▶This is an extension of spontaneous reporting program
▶ It aims to enhance ADR reporting of specific medicines in
early post marketing phase
▶ The procedure is usually followed for new drugs,
biological
medicines and for medicines that require additional
studies
▶ Example: Antiretroviral medicines under a separate
program
Targeted spontaneous reporting
▶ This method is used to learn more about ADR profile of a
specific medicine in the population
▶ To estimate the incidences of a known ADR for a specific
medicine in a population
▶ Example: Monitoring renal toxicities related to the use of
tenofovir based regimen in antiretroviral therapy
Active surveillance
▶ Sentinal sites: It involves the collection of AE data from
only part of the total population to learn something about
the larger population. Example: to study the trends in a
disease.
▶ Drug event monitoring: The patients are identified from
electronic prescription data or automated health
insurance claims. Patients will fill the survey form. Follow up
questionnaire is then sent to prescribing physician.

▶ Registries: A registry is a list of patients with the same
charateristics. This charate. The registries may be disease
specific (disease registry) or drug specific (drug registry)
or type of exposure during a specific life event (pregnancy
exposure registry). The information is collected using
standardized questionaires.
Comparative observational studies
▶ Cross sectional study: The data collected from a
population of patients can be attributed at a single point
of time/time interval regardless of exposure or disease
status.
▶ Case control study: Cases/patients of AEs are identified
from an existing data baseor using data collected
specifically for the purpose of the study.
▶ Cohort studies
Cohort event monitoring
▶Cohort means a group of people who share a common
characteristic such as exposure to a drug within a defined
time period.
▶ It is a prospective observational cohort study of adverse
events associated with one or more medicines.
▶ The study is planned prior to beginning of the treatment
with the medication.
▶ Every patient is followed up for adverse events since the
time of treatment.
▶ All adverse events are recorded.
▶ Example: ADR monitoring of anti-retroviral drugs.

Cohort event monitoring
Pros Cons
Effective in early detection of
signals of unsuspected ADRs
Method is more laborious than
spontoneous reporting method
Availability of denominator
information allows calculation of
incidence rates of ADRs
Ability to produce a near complete
profile of adverse events or ADRs
for the medicines of interest
Ability to identify and assess risk/risk
factors
Ability to make accurate
comparisons between medicines
More expensive method than
spontaneous reporting
Training is necessary
Long term follow up needs to be
actively managed

WHODrug
WHODrug China
WHO Drug Enhanced
WHO Drug Dictionary
General information
The WHO Drug Dictionary contains data from 1968 onwards
The content today is originating mostly from IMS health and
National Drug names References.
No entries are deleted even though they are withdrawn
from the market, since old case reports might be coded
with these products.
They are marked as OLD FORM
WHO Drug portfolio
WHODrug SDG
WHODrug ATC5
WHODrug Browser
WHODrug Japan CRT
WHODrug CAT
WHO Drug Change Analysis Tool (CAT)
CAT enables users to analyze the impact of data changes
from one version of WHODrug to another.
This web-based tool will give the user a complete, clear and
easy-to-understand overview of dictionary changes,
displayed in straightforward detail, record by record.

From March 2017, users are able to compare a version of the
B2-format with the same or a later B3-format release and
to view all modifications and deletions between the
selected versions.
WHO Drug Standardized Drug Groupings
(SDGs)
WHODrug SDGs provide information on how a specific class
of drugs may affect the study drug, causing unknown
interactions, protocol violations and deviations, and
unreported adverse effects.
Investigators create inclusion/exclusion drug lists as part of
the study protocol to monitor medications taken by
patients during a clinical trial. Creating and maintaining
these drug lists is time consuming and there is a risk that
relevant new drugs may be missed during the updating
process.
UMC has taken the responsibility to maintain and assure
the quality and timeliness of WHODrug SDGs, ensuring they
are unbiased and standardized drug lists. Using the SDGs
saves time for users and contributes to patient safety.
WHO Drug Insight, the new WHO
Drug browsing tool
WHODrug Insight is a tool to investigate drug properties and
increase coding efficiency.
WHODrug Insight, the new WHODrug browsing tool, was
developed to increase efficiency when coding and
analyzing medications in clinical trials and safety.
The tool makes it easier to discover new drug properties
and to work with Standardized Drug Groupings (SDGs), and
also allows creating, editing and storing Customized Drug
Groupings (CDGs) for more efficiently.

WHO DDE) is the most comprehensive and actively used
drug coding reference work in the world.
WHO DDE meets the expressed need for a consistent drug
dictionary and exact terminology when coding concomitant
medications to accelerate submissions to national
regulatory authorities.
WHO DDE contains codes for identifying drug names and
evaluating medicinal product information, including active
ingredients and therapeutic uses.
WHO DDE also reveals a product’s Anatomical and
Therapeutic use as well as its Chemical class using the ATC
classification system.
WHO Drug Cross Reference Tool (CRT)
Japan
WHODrug Cross Reference Tool Japan converts Japanese
IDF codes into WHODrug codes.
WHODrug CRT Japan thus offers companies active in Japan
a simple solution for conversion of IDF coded information
when submitting concomitant medications to the PMDA.
WHO Drug Dictionary Enhanced (WHO DDE)
WHO Drug Enhanced:
A source of international drug names
Holds information on trade name, active ingredient, MAH
holder, strength etc.
Up to date Entry
For instance: Loxonin when searched will yield below ATC
codes:

WHO Drug Herbal
Scientific binomial names and common names of
medicinal plants
Different parts and extracts of medicinal plants
Each plant/product is assigned at least one ATC/HATC code
For instance: Aloe Vera when searched, it yields below ATC
codes:
WHO Drug Global Chinese
Standardized Chinese medicinal product information, for
drug coding and safety analysis.
For drugs approved in China, product names appear in
Chinese. In addition, active substances, ATC classification,
country of sale, marketing authorization holder, and
pharmaceutical form are shown in Chinese.
For drugs approved outside China, all the above information
is provided in Chinese, except for the trade name and
marketing authorization holder, which are shown in English.
Continuously updated aligned with English version of WHO
Drug Global and with new release twice yearly.

WHO Drug KODA
WHO Drug Koda is an automated coding service custom-
built by UMC.
The service is specifically designed for increasing the
efficiency, consistency and quality of drug coding, with the
end goal of safer use of medicines.
Two formats are majorly available
for WHODrug
WHO DRUG DICTIONARY C3
B2
Trade name
Generic name
Drug code
ATC code for the drug
B2 format will have information
about the:
Trade name
Generic name
Drug code
Countries where MAH is held
Name of MAH
Different formulations available
Standard doses
ATC code for the drug
C format will have information about
the:
Non-unique names – the name appears more than once in the B2
format – with different active ingredients or
When Form or strength information is relevant in analysis

Types of medicinal products in WHO-DD
The majority of the entries refer to conventional
(chemical substance) medicinal products but the WHO-
DD also includes:
Herbal remedies
Vaccine
Blood products
Homeopathic remedy
Dietary supplement
Codes and IDs
The Drug Code is the unique key in the B2 format and it is
used also in the C format.
Unique identifier of a Product name
The code gives you information about the:
Active ingredient(s)
Salt or ester variants of the ingredient
The Drug name
1.
2.
3.
The code can be used as a key in the case report or clinical
data
The Drug Code is an aggregation of:
Drug Record Number (Drecno)
Sequence Number 1
Sequence Number 2
1.
2.
3.

Codes and IDs (Examples)
Drug Code Drecno Seq 1 Seq 2 Name
00000501001
00000501002
00000501003
00000502001
00000503002
000005
000005
000005
000005
000005
01
01
01
01
01
001
002
003
001
02
Ampicillin
Ampicin
Binotal
Ampicillin
sodium
Polycillin-n
ATC in WHO Drug Dictionary
The ATC system is maintained by the WHO Collaborating
Centre for Drug Statistics Methodology.
Part of the Norwegian Institute of Public Health1.
ATC = Anatomical Therapeutic Chemical
It serves as a tool for drug utilization research in order to
improve quality of drug use.
Applicable to both single and multiple ingredient drugs.
Medicinal products are classified according to the main
therapeutic use.
Revised yearly.

ATC Classification Main Groups
5 ATC levels
ATC codes Names

N
N02
NO2A
NO2AA
NO2AA01
Nervous system (1 st level Anatomical main group)
Analgesics (2nd Therapeutic subgroup)
Opioids (3rd pharmacological subgroup)
Natural Opioid alkaloid (4th chemical subgroup)
Morphine (5th level chemical substance)

General principles for ATC classification
(continued)
For instance: duloxetine - one ATC
Overlapping
Dosage
Antidepressant
N06AX
If clearly different indication and dosage, more than one
ATC per route can be assigned.
For instance: Finasteride – two ATCs
Different Dose
Other
dermatological
D11AX (1 mg/day)
Testosterone-5-alpha
reductase inhibitors
G04CB (5 mg/day)

General principles for ATC classification
(continued)
Only one ATC per administration route For instance:
Prednisolone

General principles for ATC classification
Summary
The system is intended for drug utilization research and not for
listing all indications for each medication.

WHO - ART
WHO- Adverse reaction terminologies
Developed for the WHO Drug Monitoring Programme
• One of the old adverse term dictionary in use since 40 years.
• Specifically for adverse reaction monitoring.
• Used by both regulatory agencies and pharmaceutical
manufacturers.
• Maintained by the UMC.
4 level hierarchical structure.
• New terms added when necessary.
• Created in English.
• Translations in French, German, Italian, Spanish, Portuguese
(Chinese, Japanese, Korean, Russia).
• Paper print, CD and electronical version.
• Latest version available in VigiSearch (and VigiFlow).
Background
WHO –ART MedDRA
Developed by WHO.
Maintained by UMC.
In use over 40 years.
New versions releases
year twice yearly.
Developed in 5
languages
Developed by ICH.
Maintained by MedDRA-
MSSO.
In use since approx. 15 years.
New version releases every
March.
Developed in 11 languages

WHO-ART Structure
System Organ
Class (SOC)
High level term
(HLT)
Preferred term
(PT)
Included term
(IT)
Group of preferred terms pertaining to the
same body organs (23)
Group Principal terms for coding and
presentation (350)
Presentation of similar preferred terms (2,256).
Terms similar to preferred terms (6048)
Difference between MedDRA and
WHO-ART structure
System Organ Class (SOC)
High level group term (HLGT)
High level term (HLT)
Preferred Term (PT)
Low Level Term (LLT)
System Organ Class (SOC)
High Level Term (HLT)
Preferred Term (PT)
Included Term (IT)

Features of MedDRA in comparison
to WHO-ART
More terms in MedDRA.
–More fine granular
–Easier to give correct description of a reaction
More levels in MedDRA.
–Other interesting levels for statistical analysis
SMQs (Standardized MedDRA Queries).
–To simplify analysis when using MedDRA.
ICH MedDRA Points-to-Consider Documents.
–Developed to facilitate consistent input and output.
WHO-ART hierarchy Example 1
SOC
Musculo-skeletal system disorders
HLT
Arthropathy
PT
Arthritis

PT
Arthropathy
IT
Joint inflammation
IT
Osteoarthritis
IT
Polyarthropathy
IT
Joint Dysfunction

WHO-ART hierarchy Example 2
MedDRA/WHO-ART grouping
Given the differences, how can MedDRA and WHO-ART be
used in parallel.
–Reports are always coded on PT/LLT level, same as for
WHO-ART where PT/IT is used.
–Multiple MedDRA terms can correspond to the same
WHO-ART term (and in rare cases vice versa).
–Some MedDRA terms representing indications, non ADR
events and laboratory tests must be mapped to a generic
WHO-ART term.
The above considerations result in what we call a
“Grouping Structure”.

Introduction to MedDRA Dictionary
Agenda
Introduction
History of MedDRA
Objectives of MedDRA
Scope of MedDRA
Hierarchy levels in MedDRA
Uniaxial
Multi-Axial terminology
Non-current terms in MedDRA.
MedDRA Codes and Languages
Examples of MedDRA Coding
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
What is medDRA?
med= Medical
D= Dictionary for
R= Regulatory
A= Activities
An ICH Standard Medical Terminology
Introduction (1/2)
The Medical Dictionary for Regulatory Activities terminology
(MedDRA) was designed for sharing regulatory information
for human medical products.
MedDRA is revised bi-annually, the main release is in the
month of March and other release is in the month of
September.

However in the month of September changes are made
only at PT’s and LLT’s levels only.
The companies will have 2-month timelines to update their
data base as per the current version of MedDRA.
Maintenance and Support Services Organization (MSSO):
its key function is to maintain, distribute, and support
MedDRA on behalf of MedDRA users.
Introduction (2/2)
Multilingual MedDRA:
The users of MedDRA have found it to be such an important
tool that, in addition to the English Master, it has been
translated into Chinese, Czech, Dutch, French, German,
Hungarian, Italian, Japanese, Korean, Portuguese,
Portuguese - Brazilian, Russian, and Spanish.
Multiple languages allow most users to operate in their
native language which promotes accuracy and precision
of assigning terms.
This interoperability is very powerful and allows easy
multinational sharing of data.
Essential supporting documentation is maintained with
each release of MedDRA in all the languages.
History of MedDRA (1/2)
The following significant milestones led to the initial release of
MedDRA:
1990 - No standard international medical terminology
1993 - Working party of EU regulatory authorities and industry
representatives reviewed and amended the UK terminology
then called MEDDRA.

October 1994 - ICH adopted MEDDRA Version 1.0 as basis for
international terminology. An ICH M1 Expert Working Group was
formed to further develop the terminology.
February 1996 - Version 1.0 was released for alpha testing by
pharmaceutical companies and regulatory authorities.
July 1997 -  ICH agreed to the Version 2.0 and renamed the
terminology MedDRA for Medical Dictionary for Regulatory
Activities.
History of MedDRA (2/2)
May 1998 -  ICH Assembly established the ICH MedDRA
Management Committee.
November 1998 -  MedDRA Maintenance and Support Services
Organization (MSSO) was contracted to maintain and support
MedDRA by IFPMA as a trustee of ICH.
January 1999 -  Japanese Maintenance Organization (JMO)
was established.
March 1999 - Initial version of MedDRA (Version 2.1) was
available from the MedDRA MSSO and the Japanese version
from the JMO.
Objectives for MedDRA Development
An international multi-lingual terminology.
Standardized communication between industry and
regulators.
Support of electronic submissions.
Application through all phases of the development cycle.
Classification for a wide range of clinical information.
Support for multiple medical product areas.
A terminology that saves time, resources, and money.

In and Out scope of MedDRA
Out of scope:
Not a drug dictionary
Not for patient demographics
Not a diagnostic product dictionary
Not an equipment dictionary
Not Severity descriptors
Numerical values for results
Frequency qualifiers
CT study design terms
IN SCOPE:
Medical conditions.
Indications.
Investigations (test and results)
Medical and surgical procedures.
Medical, Social, and family history.
Medication errors.
Product quality issues.
Device related issues
Pharmacogenetic terms.
Toxicologic terms.
Standardized queries

MedDRA Hierarchy (5 level hierarchy)system
According to MedDRA 24.0 (released on 01-Mar-2021)
Lists of SOC (System Organ Class) (1/2)
Anatomical functional body system.
Etiology (infection and infestation SOC’s)
Purpose (Surgical or medical procedural SOC’S)
Top level hierarchy, the broadest concept of standardized
terminologies, used for data grouping.
SOC’s reflects
Lists of SOC (System Organ Class) (2/2)
Blood and lymphatic system disorders
Cardiac disorders
Congenital, familial and genetic disorders
Ear and labyrinth disorders
Endocrine disorders
Eye disorders
Gastrointestinal disorders

General disorders and administration site conditions
Hepatobiliary disorders
Immune system disorders
Infections and infestations
Injury, poisoning and procedural complications
Product Issues
Investigations
15. Metabolism and nutrition disorders
16. Musculoskeletal and connective tissue disorders
17. Neoplasms benign, malignant and unspecified (incl cysts
and polyps)
18. Nervous system disorders
19. Pregnancy, puerperium and perinatal conditions
20. Psychiatric disorders
21. Renal and urinary disorders
22. Reproductive system and breast disorders
23. Respiratory, thoracic and mediastinal disorders
24. Skin and subcutaneous tissue disorders
25. Social circumstances
26. Surgical and medical procedures
27. Vascular disorders
HLGT (High Level Group Term)
HLGT are broad level terminologies directly under the SOC’s
and composed of HLT’S.
HLGT’s group related HLT’S by anatomy, physiology, etiology,
pathology and functions.
HLGT’S are used for data retrieval, data analysis and
presentations.

PT’s are the unique medical concept that stands alone.
Regulatory authorities exchange information at PT level.
An identical current several LLT’s link to a single PT.
PT’s with component of various LLT’s can fall in different
SOC’s.
Forming a multiaxial pattern of MedDRA structure.
Which makes MedDRA complex but at same time versatile
and sophisticated with accuracy in medical concepts,
however medical judgement is always essential while
coding.
HLT (High Level Term)
High level term are directly under HLGT’S and above PT’S.
An HLT groups relates the PT’s anatomy, physiology,
etiology, pathology and functions.
The HLT’s represents medical entities that are detailed by a
distinct, unique concepts expressed by the PT’s.
HLT’s are also used for data retrieval, data analysis and
presentations.
PT (Preferred Term)
Hierarchy Of SOC- HLGT- HLT- PT- LLT’s

Low Level Terms (LLT)
The LLT’s are just different ways of expressing a medical
concept.
The LLT’s are coded to closest PT’s
The more than one LLT can be linked to single PT
The LLT’s linked to same PT’s can be:
Laxical variant, (ex: PT: Acquired immunodeficiency
syndrome, LLT: AIDS)
Synonyms (e.g., PT Arthritis and its subordinate LLT Joint
inflammation)
American and British spellings
May express aggravation concepts.
LLT’s can be current or non-current.
Example

Non-current terms
Non-current terms are flagged at the LLT level within
MedDRA.
Not recommended for continued use.
Retained within the terminology to preserve historical data
for retrieval and analysis.
Terms very vague, ambiguous, outdated, truncated, or
misspelled.
Terms derived from other terminologies that do not fit
MedDRA rules.
MedDRA Codes and Languages
Each MedDRA term is assigned an 8-digit numeric code,
which are non-expressive
Codes can fulfill a data field in various electronic
submission types (e.g., E2b).
Initially assigned alphabetically by term starting with
10000001.
New terms are assigned sequentially.
Supplemental terms are assigned codes.
Terms are being renamed and the code number is reused
for the renamed term.
Renaming would be done for spelling errors, hyphenation,
and parenthesis changes.
When HLT or HLGT terms are removed from the
terminology, they are deleted – NOT moved to the LLT level
and made non-current.

MedDRA Codes and Languages (2/2)
Uniaxial
It is a representation of a medical concept in a single SOC
SOC Investigations, SOC Social circumstances, and SOC
Surgical and medical procedures are single-axial SOC.
Example:

Multi Axial terminology (1/3)
Allows grouping by different classifications
Allows retrieval and presentation via different data sets
All PTs assigned a primary SOC
Prevents “double counting”
Supports standardized data presentation
Pre-defined allocations should not be changed by users
Multi-axial = the representation of a medical concept in
multiple SOCs
Determines which SOC will represent a PT during cumulative
data outputs
Multi Axial terminology (2/3)

Multi Axial terminology (3/3)
Example:
Rules for Primary SOC Allocation
PTs represented in only one SOC are automatically
assigned that SOC as primary
PTs for diseases, signs and symptoms are assigned to
prime manifestation site SOC
Congenital and hereditary anomalies terms have SOC
Congenital, familial and genetic disorders as Primary SOC
Neoplasms terms have SOC Neoplasms benign, malignant
and unspecified (incl cysts and polyps) as Primary SOC
Exception: Cysts and polyps have prime manifestation
site SOC as Primary SOC
Infections and infestations terms have SOC Infections and
infestations as Primary SOC

Primary SOC Priority
If a PT links to more than one of the exceptions, the following
priority will be used to determine primary SOC:
1 st : Congenital, familial and genetic disorders.
2 nd : Neoplasms benign, malignant and unspecified (incl
cysts and polyps).
3 rd : Infections and infestations.
Points to consider
A single letter difference in a reported verbatim text can
impact the meaning of the word and consequently the
term selection.
Example: Reported LLT Selected.

Examples
Do Not Add Information
Do not make diagnosis if only signs/symptoms
reported:

Few Examples
Single Diagnosis Examples

Examples
Thumb Rules (1/2)
Select a Lowest Level Term that most accurately reflects the
reported verbatim information.
Non-current LLTs should not be used for term selection.
When considering selecting an LLT, check the hierarchy
above the LLT (PT level and further up the hierarchy to HLT,
HLGT and SOC) to ensure the placement accurately reflects
the meaning of the reported term.
If two conditions are reported in combination, and one is
more specific than the other:
E.g. Arrhythmia due to atrial fibrillation code LLT atrial
fibrillation.

Thumb Rules (2/2)
Splitting terms:
Example: Hernia worsened, code LLT’s Hernia and Condition
aggravated.
Multiple body sites:
Example: Skin rash on face, neck – LLT Skin rash.
Combination Terms: When 2 different medical concept can be
expressed in a single code:
Tip: condition “due to” another condition OR “secondary to”
E.g. Retinopathy due to diabetes – select Diabetic retinopathy
Revision History

Periodic Safety Update Report
Need for PSUR
Limited No. Of patients in clinical trial
Exclusion of certain patient at risk
Lack of significant long term treatment
Limitation of concomitant medication
Closely Monitored
Priorities will be
given to both
serious and
unexpected during 1st year of
commercialization
Surveillance of marketed Drugs
RA
MAH

PSUR
Record drug information
from different resources
Timely detection and mutual
exchange of safety data
Why PSUR?
Relevant new safety information
Relate data to patient exposure
Significant variation in demography related to safety
Periodic opportunity for overall safety evaluation
Whether changes required in PI
Timelines for PSUR

General Principles
One report for active substance
All dosage form and formulation in one PSUR
Fixed combination drugs
General Scope of information
All clinical and nonclinical safety data
ADR not AE
Spontaneous Reports
Clinical study and literature cases
Lack of efficacy
Increase in frequency of documented ADR
International birth date
International Birth Date Date of first marketing authorization for
the product granted to any company in any country MAH
Submit PSUR within 60 days of data lock point
Reference Safety Information
CCDS-Company Core Data Sheet
CCSI-Company Core Safety Information
Listed
Unlisted
Expectedness

Source of Information
Direct report to MAH
Literature
ADR Reporting of Regulatory Authorities
Epidemiological database
Line listing and summary Tabulation
Individual case line listing
Summary Tabulation
All serious ADRs
All non serious unlisted ADRs
All non serious listed ADRs
Sample PSUR
Periodic Safety Update Report for Product
MAH name and address
Period covered by this report
International Birth Date
Date Of Report
Table Of Content
Introduction
World Wide Market Authorization Status
Update of Regulatory Authority or MAH action taken for safety
reason
Patient Exposure
Presentation of Individual case histories
Studies
Other information
Overall Safety Evaluation

Introduction
This is a PSUR of Paracetomol covering the period
____________t0_____________
The report summarizes all adverse reaction reported in
connection of ABC Pharma
ABC PARAT got approval for 500mg and 650mg
World wide market authorization status
Date of marketing Authorization
Limits of indication and safety
Treatment indication and Population Covered
Lack of Approval
Withdrawal
Launch Date
Trade name
Update of Regulatory Authority
MA Withdrawal and Suspension
Failure to obtain marketing authorization
Clinical trial suspension
Dosage Modification
Change in target population or indication
Formulation change
Reference safety information
Changes to CCSI
New Contraindication
New Precaution
New Warning
New ADR
New Reaction

Patient’s exposure
Number of prescribed drugs.
Number of drugs sold.
Presentation of the line listing
MAH case reference number
Country
Source
Age & sex
Daily dose
Date of onset
Description of event
Patient outcome : resolved, fatal, improved, unknown
comments
Presentation of the line listing

MAH analysis of individual case histories
Brief comments on data concerning individual cases.
Unanticipated findings
Studies
Completed studies
Clinical
Nonclinical
Epidemiological
Studies specifically planned
Studies in progress
Published studies
Newly analyzed company sponsored studies
Studies containing important safety information
Study design
Study results
Clinical report
Non clinical study reports.
Published safety studies
Reports in scientific/ medical literature.
Relevant published abstracts from meeting containing
important safety finding.
Publication reference.

Other information
Efficacy related information.Product used to treat serious or
life threatening diseases. Medically relevant lack of efficacy
reporting.
Late breaking news
Any important new information received after database
was frozen for review and report preparation.
Significant new cases.
Important follow up data.
Overall safety evaluation
Concise analysis of data presented so far.
Change in characteristics of listed reaction.
Serious unlisted reaction.
Non- serious unlisted reaction.
Increased reporting frequency of listed reaction.
Overall safety evaluation
Drug interaction
Experience with overdose
Drug abuse or misuse
Positive or negative experience with pregnancy or lactation
Experience in special patient groups
Effects of long term treatment

Other countries Regulatory
timelines
Contents
Timelines for submission (excluding Japan)
Timelines for submission (for Japan)
Requirement for foreign/ domestic reports
Published Literature monitoring for ADR cases
PSUR submission requirements
PSUR submission cycles
Timelines for submission of PSUR from the Data Lock Point
(DLP)
Risk management plan submission mandatory
Timelines for submission (excluding Japan)
Variations Examples
15 calendar days
90 calendar days
10 working days for
domestic cases
5 calendar days
Serious Unexpected for US
Serious Suspected ADRs for EU
Non-Serious Suspected
ADRs for EU
Vietnam
Business Partners Exchange to
MAH

Timelines for submission (for Japan)
For Investigational products: Japanese expedited reporting
requirements
Variations Examples
7 day Fatal or life-threatening unexpected
15 day Fatal or life threatening expected
15 day
Results from clinical trials indicate
an increased frequency of ADRs, lack
of efficacy or the possibility of an
association with the onset of cancer,
important medical events,
disability/incapacity or a fatal
outcome
Timelines for submission (for Japan)
Marketed products: Japanese expedited reporting requirements
Variations Examples
15 calendar day
6 monthly
Serious unexpected local and foreign, Serious expected
local
Non-serious unexpected local
No need to report
Non-serious expected local; Non-serious unexpected
foreign
PSURs
Drugs with NCE including similar bio-therapeutic product;
Other drugs on request by NADFC
Risk Management Plans Upon request by the NADFC

Requirement for foreign/ domestic reports
Variations Examples
Both foreign and
domestic
US, EU, Japan, Ukraine (Only
serious unexpected, fatal/
life threatening cases from
confirmed company products
Foreign reports
not required
Mexico, South Africa, Malaysia,
Brazil, Australia, Singapore,
Thailand, China, Russia
Published Literature monitoring for ADR cases
Variations Examples
Required
US, EU, Australia (domestic
only), Canada, Japan
Not Required
India, Latin America,
Africa, Russia

PSUR submission requirements
Variations Examples
Mandatory
requirement
US, EU, India
On request by
regulatory agencies
Canada, South Africa
At license
renewal only
United Arab Emirates
PSUR submission cycles
Variations Examples
Quarterly, annually
US
Quarterly, semi-annually, annually,
re-registration
Mexico
Three years (harmonized birth date
based)
EU
Annually Australia
Registration, re-registration Khazakhstan, Ukrain,
Russia, Belarus, Iran,
UAE, China

Timelines for submission of PSUR from the
Data Lock Point (DLP)
Variations
Examples
30 – 60 days (quarterly/annual)
60 days
30 days
US
EU, Brazil
India
Risk management plan submission mandatory

Variations
Examples
For all new registrations
Not mandatory for all registrations
EU
Rest of the world

Pharmacovigilance Programe in India
Introduction
Pharmacovigilance is a system to monitor the safety and
effectiveness of medicines and other pharmaceutical products.
As per WHO:
Pharmacovigilance as "science and activities relating to the
detection, assessment, understanding and prevention of
adverse effects or any other possible drug-related problems".
Background
1989 - ADR monitoring system for India proposed (12 regional
centres)
1997 - India joined WHO-ADR monitoring programme (3
centres: AIIMS, KEM, JLN)
2004-2008 - National Pharmacovigilance Programme
2010 - Pharmacovigilance Programme of India

Initiated with AIIMS, New Delhi as National Coordinat
for monitoring ADRs in the country July 2010, shifted to Indian
Pharmacopoeia Commission (IPC), Ghaziabad on 15th April
2011
Vision:
To improve patient safety and welfare of Indian population by
monitoring the drug safety and thereby reducing the risk
associated with use of medicines
Mission:
Safeguard the health of the Indian population by ensuring that
the benefits of use of medicine outweigh the risks associated
with its use

Scope and Objectives
* To create a nation-wide system for patient safety reporting
* To identify and analyze new signal from the reported cases
To analyze the benefit-risk ratio of marketed medications
*To support regulatory agencies in the decision-making
process on use of medications
* To communicate the safety information on use of medicines
to various stakeholders to minimize the risk
* To provide training and consultancy support to other
national pharmacovigilance centers across globe
* To promote rational use of medicine
Short Term Goals
To develop and implement pharmaco-vigilance system in
India
To enroll, initially, all MCI approved medical colleges in the
program covering north, south, east and west of India
To encourage healthcare professionals in reporting of
adverse reaction to drugs, vaccines, medical devices and
biological products
Collection of case reports and data

Long Term Goal
To expand the pharmacovigilance programme to all
hospitals (govt. & private) and centres of public health
programs located across India
To develop and implement electronic reporting system (e-
reporting)
To develop reporting culture amongst healthcare
professionals
To make ADR reporting mandatory for healthcare
professionals

1. Spontaneous Reporting
A spontaneous report is an unsolicited communication by healthcare
professionals or consumers to a company, regulatory authority or
other organisation (e.g., WHO, CDSCO etc) that describes one or more
adverse drug reactions in a patient who was given one or more
medicinal products and that does not derive from a study or any
organised data collection scheme
Spontaneous reporting system under PvPI
Electronic reporting: Electronic transmission of ICSRs from ADR
Monitoring Centers to National Coordination Centre through VigiFlow
(WHO Global Safety Database).
Voluntary reporting: Submission of ICSRS to the National Coordination
Centre by Pharmaceutical companies or health care professionals.
Peripheral reporting: Submission of ICSRs by hospitals, healthcare
clinics, health care professionals, patient to the nearest ADR Monitoring
Centre.
Spontaneous reporting

Objective: A prospective, longitudinal, observational, cohort
study of adverse events associated with one or more
monitored medicines.
It is related to class of medicine that has previously caused
ADRs
Potentially significant adverse event observed during post-
marketing surveillance
2. Targeted Spontaneous Reporting
Objective:
To learn more about the ADR profile of specific medicine(s) in
your population
Or
To estimate the incidence of a known ADR to a specific
medicine in your population
3. Cohort Event Monitoring

Comparing the PV Methods
Organization Committees under
Steering Committee
PVPI Working Group
Quality Review Panel
Signal Review Panel
Core training panel
NCC Working Module
Letter of intent from AMCS Coordinator
NCC-PVPI
Examine the Suitability
Approved by NCC
Vigi-Flow login details provided by NCC to AMCs
AMCS-To perform the causality assessment of the ADRs and furnish
the mandatory fields in the suspected ADRs form
AMCs - upload the ADRs in Vigi-Flow
NCC-PVPI
Send to

Collection of ADR reports
Perform follow up with the complainant to check
completeness as per SOPS
Data entry into Vigiflow
Reporting to PvPI National Coordinating Centre (PvPI NCC)
through Vigiflow with the source data (original) attached
with each ADR case
Training/sensitization/ feedback to physicians through
newsletters circulated by the PvPI NCC
Responsibilities of Stakeholder
Personnel at AMC
Personnel at NCC
Preparation of SOPs, guidance documents & training
manuals
Data collation, Cross-check completeness, Causality
Assessment etc as per SOPS
Conduct Training workshops of all enrolled centers
Publication of Medicines Safety Newsletter
Reporting to CDSCO Headquarters
Analysis of the PMS, PSUR, AEFI data received from CDSCO
HQ

Personnel at Zonal/ Sub-zonal CDSCO
Provide procurement, financial and administrative
support to ADR monitoring centers
Report to CDSCO HQ
Personnel at CDSCO HQ
Take appropriate regulatory decision & actions on the
basis of recommendations of PvPI NCC at IPC Ghaziabad.
Propagation of medicine safety related decisions to
stakeholders
Collaboration with WHO-Uppsala Monitoring Center -
Sweden
Provide for budgetary provisions & administrative support
to run PVPI

Phases or Road Map of PvPI
►Initiation phase (2010-2011)
▶Expansion and consolidation phase (2011-2012)
▶Expansion and maintenance phase (2012-2013)
▶Expansion and optimization (2013-2014)
▶Excellence phase (2014-2015)

VIGIFLOW
Vigiflow is an Individual Case Safety Report (ICSR)
management system developed and hosted by Uppsala
monitoring centre (UMC).
The minimum information you have to enter on a
spontaneous report for it to be considered 'complete' by
VigiFlow is the following six mandatory fields:
1) Report title
2) Patient initial
3) Patient age (either date of birth, age at time of onset
age group)
4) Onset date of reaction (year only)
5) Reaction term
6) Drug name

Basics of signal detection and
introduction to surveillance
Agenda
Signal definition
Signal Management Process
Steps in Signal Management
Signal management flow chart
Common sources of Signal
Monitoring of EudraVigilance data
Periodicity of monitoring
SigTRACE tool
EudraVigilance data analysis system
Signal definition
Information that arises 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 significant 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.

Signal Management Process
A set of activities performed to determine whether, based on
an examination of individual case safety reports (ICSRs),
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.
Steps in Signal Management
Signal detection
Signal validation
Signal confirmation
Signal analysis and prioritization
Signal assessment
Recommendation for action
Signal management flow chart

Common sources of Signal
Spontaneous reports, Literature and media
Clinical trails, registries, post-approval named patient use
programs, other patient and disease management programs
Inter-company agreement of safety information
ICSRs, Suspected Unexpected Serious Adverse Reactions
(SUSARs), Pharmacovigilance Risk Assessment Committee
(PRAC), aggregate reports and Risk Management Plan (RMP)
commitments.
Unsolicited sources
Solicited sources
Contractual agreements
Regulatory authority
Signal detection
Is the process of looking for and/or identifying signals using
data from any source. Broadly classified into two categories
(CIOMS VIII)
Encompass manual medical review of individual cases, case
series, and reporting rates.
These methods usually include computer-aided statistical
methods and data mining algorithms based on 2×2
contingency tables producing disproportionality analysis.
Traditional methods
Enhanced quantitative methods

Signal validation
The 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.
Signal validation outcomes
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.
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.

Signal confirmation
Confirmed signal: A validated signal that requires further
analysis and prioritization.
Non-confirmed signal: A validated signal that does not
require further analysis and prioritization at that point in
time.
It is the process of deciding whether or not a validated signal
requires further analysis and prioritization. Signal confirmation
is not intended to be a full assessment of the signal.
Signal analysis and prioritization
This is 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.
This process also determines whether a confirmed signal
requires further assessment.
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 review may
include non-clinical and clinical data and should be as
comprehensive as possible regarding the sources of information.
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.

Recommendation for action
Periodic review of the signal
Risk minimization activities
Update of the product information
Post-authorization safety study
Suspending the marketing authorization
Signal assessment results in a recommendation that either no
further action is required at this point in time or a further action
is needed.
Examples of further action
Case scenario
Signal detection: A spontaneous report of Kounis syndrome with the
drug co-amoxiclav was reported to MAH. MAH assessed the event as
unlisted with probable causality and flagged it as signal (based on
the internal criteria: life threatening or fatal events with probable
causality).
Signal validation : Literature search for Kounis syndrome with the
drug co-amoxiclav returned several hits in which the drug was the
common suspect with a reasonable time relationship with the event,
suggesting a positive causal association.
Signal confirmation: Literature search results of Kounis syndrome
with co-amoxiclav were reviewed and a causal relationship was
confirmed.
Signal analysis and prioritization: Kounis syndrome might
significantly affect the risk-benefit balance of co-amoxiclav and
thus required urgent attention, further assessment, and
management without delay.
Signal assessment: Review of product information of the innovator
and other MAH for the active ingredient revealed a recent update
with Kounis syndrome added as listed event.
Recommendation for action: Information on the causal relationship
between Kounis syndrome and co-amoxicillin was informed to
regulatory authorities and the product information was updated.

Emerging safety issue
unexpectedly increased rate of fatal or life-threatening
adverse events,
major safety issues identified through spontaneous
reporting or published in the scientific literature,
restriction of the use of the medicinal product or its
suspension.
A safety issue considered by a MAH 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.
SigTRACE overview
SigTRACE is a product developed by Bioclinica to streamline
Signal Management Process within Pharma Companies.
It is a cloud-based multitenant hosted, workflow based
product that organizes Case data received from Drug
Safety systems, automates quantitative analysis and
provides workflow-based system that integrates the steps
within the Signal Management process.
It also provides custom report generation and dashboards
for better tracking of the Signal status.

SigTRACE snapshot
Monitoring EudraVigilance
On 22-Nov-2017, EMA launched the new EudraVigilance
system and enabled MAH access to the system. During a
pilot period which started on 22-Feb-2018, MAHs of the
active substances included in the list of active substances
involved in the pilot on signal detection must monitor
them in EudraVigilance and inform EMA and national
competent authorities of validated signals with their
medicines.
In Dec-2019 EMA and the European Commission agreed to
extend the pilot until the end of 2021 to generate more
robust data after reviewing the experience gained in the
first year of the pilot.

Periodicity of monitoring
MAHs shall ensure the continuous monitoring of the
EudraVigilance database with a frequency proportionate to
the identified risk, the potential risks and the need for
additional information on medicinal products or active
substances.
It is recommended to monitor EudraVigilance data at least
every 6 months.
A more frequent monitoring is recommended for active
substances contained in medicinal products included in the
additional monitoring list.
EVDAS snapshots

Key Points to remember
Signal arises 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 significant likelihood to justify verificatory
action.
Steps in Signal Management: Signal detection, Signal
validation, Signal confirmation, Signal analysis and
prioritization, Signal assessment and Recommendation for
action.
It is recommended to monitor EudraVigilance data at least
every 6 months.

PV Audit and Inspection
Fundamental steps in Audit.
Terminologies in Audit
Pharmacovigilance audit and it’s objectives
The risk-based approach to pharmacovigilance audits
Operational level audit planning and reporting
Actions based on audit outcomes and follow-up of audits
Quality system and record management practices
Content
Terminologies
Audit: An audit is a systematic, disciplined, independent
and documented process for obtaining evidence and
evaluating the evidence objectively to determine the
extent to which the audit criteria are fulfilled.
Audit Finding: The result of the evolution of the collected
audit evidence against audit criteria. That is nothing but
auditor’s opinion and reports.
Audit Plan: Description of activities and arrangement for an
individual audit.
Audit program: Set of one or more audit planned for
specified time frame directed towards specific purpose.

Terminologies (Contd….)
Auditee: entity being audited.
Compliance: Conformity and adherence to policies, plans,
procedures, laws, regulations, contracts, or other
requirements.
Control: Any action taken by management and other
parties to manage risk and increase the likelihood that
established objectives and goals will be achieved.
Management plans, organizes, and directs the
performance of sufficient actions to provide reasonable
assurance that objectives and goals will be achieved.
Evaluation (of audit activities): Professional auditing bodies
promote compliance with standards, including in quality
assurance of their own activities, and codes of conduct,
which can be used to address adequate fulfilment of the
organization's basic expectations of Internal Audit activity
and its conformity to internationally accepted auditing
standards.
Auditor's independence: The freedom from conditions that
threaten objectivity or the appearance of objectivity. Such
threats to objectivity must be managed at the individual
auditor, engagement, functional and organizational levels.
Auditor's objectivity: An unbiased mental attitude that
allows internal auditors to perform engagements in such a
manner that they have an honest belief in their work
product and that no significant quality compromises are
made. Objectivity requires internal auditors not to
subordinate their judgment on audit matters to that of
others.

Fundamental steps in Audit
Pharmacovigilance audit and it’s objectives
Pharmacovigilance audit activities should verify, by
examination and evaluation of objective evidence.
The appropriateness and effectiveness of the
implementation and operation of a pharmacovigilance
system, including its quality system for pharmacovigilance
activities.
Audit evidence consists of records, statements or other
information, which are relevant to the audit criteria and
verifiable.
Audit criteria for each audit objective, the standards of
performance and control against which the Auditee and its
activities will be assessed.

The risk-based approach to
pharmacovigilance audits
A risk-based approach uses techniques to determine the
areas of risk,.
The risk-based approach to audits focuses on the areas of
highest risk to the organization's pharmacovigilance system,
including its quality system for pharmacovigilance activities.
The context of pharmacovigilance, the risk to public health
is of prime importance
Strategic level audit planning “audit strategy” (long term approach)
is endorsed by upper management.
Tactical level audit planning “audit program”, setting audit objectives,
and the extent and boundaries, often termed as scope, of the audits
in that program.
Operational level audit planning “audit plan” for individual audit
engagements, prioritizing audit tasks based on risk and utilizing risk-
based approaches, and reporting of audit findings in line with their
relative risk level and audit recommendations in line with the
suggested grading system.

The risk-based approach
topharmacovigilance audits Strategic
level audit planning
The audit strategy should cover the governance, risk
management and internal controls of all parts of the
pharmacovigilance system including:
• All pharmacovigilance processes and tasks
• The quality system for pharmacovigilance activities
• Interactions and interfaces with other departments, as
appropriate
• Pharmacovigilance activities conducted by affiliated
organizations or activities delegated to another organization
(e.g. regional reporting centers, MAH affiliates or third parties,
such as contract organizations and other vendors).
Changes to legislation and guidance.
Major re-organization or other re-structuring of the
pharmacovigilance system, mergers, acquisitions.
Change in key managerial function.
Risk to availability of adequately trained and experienced
pharmacovigilance staff.
Examples of risk factors that could be considered for the
purposes of a risk assessment:

Significant changes to the system since the time of a
previous audit (e.g. introduction of a new database(s) for
PV activities or of a significant upgrade to the existing
database(s), changes to processes and activities in order
to address new or amended regulatory requirements).
First medicinal product on the market.
Medicinal product(s) on the market with specific risk
minimization measures or other specific safety conditions
such as requirements for additional monitoring.
For national medicines authorities: How critical is the
area/process to proper functioning of the
pharmacovigilance system and the overall objective of
safeguarding public health.
For MAH: How critical is the area/process to proper
functioning of the pharmacovigilance system. When
deciding to audit an affiliate or third party, the MAH should
consider the nature and criticality of the
pharmacovigilance activities.
If the area/process has previously been audited, the audit
findings are a factor to consider when deciding when to re-
audit the area/process, including the implementation of
agreed actions.
For national medicines authorities: Information from
compliance metrics from complaints, from external
sources, e.g. audits/assessments of the national medicines
authority that may be conducted by external bodies;
For MAH : Information from compliance metrics from
inspections, from complaints, from other external sources,
e.g. audits;
Other information relating to compliance with legislation and
guidance, for example:

Other organizational changes that could negatively impact on the
area/process, e.g. if a change occurs to a support function (such as
information technology support) this could negatively impact upon
pharmacovigilance activities.
The risk-based approach to pharmacovigilance audits
Tactical level audit planning
An audit programme is a set of one or more audits planned
for a specific timeframe, normally for a year. It should be
prepared in line with the long term audit strategy. The
audit programme should be approved by upper
management with overall responsibility for operational and
governance structure.
Quality system for pharmacovigilance activities.
Critical pharmacovigilance processes.
Key control systems relied on for pharmacovigilance
activities.
Areas identified as high risk, after controls have been put in
place or mitigating action taken.
It should focus on:
Historical areas with insufficient past audit coverage high
risk areas identified by and/or specific requests from
management and/or persons responsible for
pharmacovigilance activities.
The audit programme documentation should include a
brief description of the plan for each audit to be delivered,
including an outline of scope and objectives.
The rationale for the timing, periodicity and scope of the
individual audits which form part of the audit programme
should be based on the documented risk assessment.
It should also focus on:

The risk-based approach to pharmacovigilance audits
Operational level audit planning and reporting
Planning and fieldwork
The organization should ensure that written procedures
are in place regarding the planning and conduct of
individual audits that will be delivered.
Timeframes for all the steps required for the performance
of an individual audit should be settled in the relevant
audit related procedures.
The organization should ensure that audits are conducted
in accordance with the written procedures, in line with this
GVP Modules
Individual pharmacovigilance audits should be undertaken
in line with the approved Risk-based audit program.
When planning individual audits, the auditor identifies and
assesses the risks relevant to the area under review.
The auditor also employs the most appropriate risk-based
sampling and testing methods, documenting the audit
approach in an audit plan.
Reporting
The findings of the auditors should be documented in an
audit report and should be communicated to
management in a timely manner.

The audit process should include mechanisms for
communicating the audit findings to the Auditee and
receiving feedback, and reporting the audit findings to
management and relevant parties, including those
responsible for PV systems, in accordance with legal
requirements and guidance on PV audits.

The risk-based approach to pharmacovigilance audits
Operational level audit planning and reporting
Audit findings should be reported in line with their relative risk
level and should be graded in order to indicate their relative
criticality to risks impacting the pharmacovigilance system,
processes and parts of processes.
The grading system should be defined in the description of
the quality system for Pharmacovigilance should take into
consideration the thresholds noted below which would be
used in further reporting under the legislation of EU.
The risk-based approach to pharmacovigilance audits
Operational level audit planning and reporting findings
Critical: Is a fundamental weakness in one or more
pharmacovigilance processes or practices that adversely
affects the whole pharmacovigilance 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
Major: Is a significant weakness in one or more
pharmacovigilance processes or practices, or a fundamental
weakness in part of one or more pharmacovigilance processes
or practices 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.

Minor: Is a weakness in the part of one or more pharmacovigilance
processes or practices that is not expected to adversely affect the whole
pharmacovigilance system or process and/or the rights, safety or
wellbeing of patients.
Actions based on audit outcomes and follow-up of audits
The precise timeframe for action(s) related to a given critical
finding, for example, may differ depending on nature of
findings and the planned action(s).
The management of the organization is responsible for
ensuring that the organization has a mechanism in place to
adequately address the issues arising from
pharmacovigilance audits.
Actions should include root cause analysis and impact
analysis of identified audit findings and preparation of a
corrective and preventive action plan, where appropriate.
Upper management and those charged with governance,
should ensure that effective action is implemented to
address the audit findings.
The implementation of agreed actions should be monitored
in a systematic way, and the progress of implementation
should be communicated on a periodic basis proportionate
to the planned actions to upper management.
Evidence of completion of actions should be recorded in
order to document that issues raised during the audit have
been addressed.
Capacity for follow-up audits should be foreseen in the audit
program. They should be carried out as deemed necessary,
in order to verify the completion of agreed actions.
Corrective and preventive actions to address critical and major
issues should be prioritized.

Quality system and record management practices
Independence and objectivity of audit work and auditors:
The organization should assign the specific responsibilities
for the pharmacovigilance audit activities.
Pharmacovigilance audit activities should be independent.
The organization‘s management should ensure this
independence and objectivity in a structured manner and
document this.
Auditors should be free from interference in determining the
scope of auditing, performing pharmacovigilance audits
and communicating audit results.
The main reporting line should be to the upper
management with overall responsibility for operational and
governance structure that allows the auditor(s) to fulfil their
responsibilities and to provide independent, objective audit
opinion.
Auditors can consult with technical experts, personnel
involved in pharmacovigilance processes, and with the
person responsible for pharmacovigilance.
Auditors should maintain an unbiased attitude that allows
them to perform audit work in such a manner that they
have an honest belief in their work product and that no
significant quality compromises are made.
Objectivity requires auditors not to subordinate their
judgment on audit matters to that of others.

Qualifications, skills and experience of auditors
& continuing professional development
Audit principles, procedures and techniques,
Applicable laws, regulations and other requirements
relevant to pharmacovigilance,
Pharmacovigilance activities, processes and system(s),
Management system(s),
Organizational system(s).
The proficiency of audit team members will have been gained
through a combination of education, work experience and
training and, as a team, should cover knowledge, skills and
abilities in:
Evaluation of the quality of audit activities
Evaluation of audit work can be undertaken by means of
ongoing and periodic assessment of all audit activities, Auditee
feedback and self-assessment of audit activities.
(e.g. quality assurance of audit activities, compliance to code of
conduct, audit program, and audit procedures).
Some examples of audits
Database/Data Audit
Functional/Department Area Audit
GCP Compliance Audit
GVP Compliance Audit
Pharmacovigilance System Master File (PSMF) Audit
The following are examples of the types of audits that can be
performed, but are not limited to:

Product-Specific/Project-Specific/Study-Specific Audit
Pre-Inspection/Inspection Readiness Audit
Process/System Audit
Summary of Pharmacovigilance Systems (SPS) Audit
Audits undertaken by outsourced audit service providers
The requirements and preparation of the audit risk
assessment, the audit strategy and audit program and
individual engagements should be specified to the
outsourced service providers, by the organization, in writing.
The scope, objectives and procedural requirements for the
audit should be specified to the outsourced service
provider, by the organization, in writing.
The organization should obtain and document assurance
of the independence and objectivity of outsourced service
providers.
The outsourced audit service provider should also follow
the relevant parts of this GVP module.
Where the organization decides to use an outsourced audit
service provider to implement the pharmacovigilance audit
requirements on the basis of this GVP module and perform
pharmacovigilance audits:-

Pharmacovigilance Inspection
To verify that the applicant has personnel, systems &
facilities in place to meet the regulatory obligations for
Approved Products.
To confirm that the Pharmacovigilance system is
functional, complies with requirements & is consistent with
the guidelines.
To check whether the safety information included in a
Approved Product dossier and related product information
(SPC, PIL etc.) appears credible and accurate.
To help applicant to improve compliance.
To use the inspection results as a basis for enforcement
action.
Inspection is an audit coverage to check if a company satisfies
the requirements prescribed by laws and directives
concerning the safety of authorized medicinal products with
attention.
Objectives Of Inspection
Types of Inspections
System and product-related inspections
Routine and “for cause” pharmacovigilance inspections
Pre-authorization inspections
Post-authorization inspections
Announced and unannounced inspections
Re-inspections
Remote inspections.
As per GVP Module iii there are 7 types of inspections that can
be carried out.

Types of Inspections
FDA
Surveillance: Routine FDA inspection every 2 years,
concentrating on basic FDA requirements (i.e., GMP
compliance).
Compliance: Based on specific objective like- suspected
problem, such as unreported AEs and also occurs as a follow-
up to a previous violative surveillance inspection
EMA Inspection
EMA informs applicant of the adopted inspection request
within 5 working days of the CHMP giving details of the
inspection team and the fees.
EMA informs the inspectorates and finalizes the
designation of the inspection team (reporting and lead
inspectorates).
Inspectors contact applicant and sites to be inspected
and schedule inspection dates and request any additional
documents needed (e.g. SOPs)
The inspectors make the arrangements with the inspectee
and fix an inspection date, which should be carried out
within the proposed timetable.
At the end of the inspection, the inspectors make a report
of the main findings to the company inspected.
The deficiencies observed are classified as critical or non-
critical with references to legislation and guidelines such
as the EU Guide, to ICH guidelines and/or national
legislation.

The Inspection Report is sent to the company with a request
for comments on major factual errors, points of
disagreement or remedial actions to be provided within 15
calendar days of receipt.
Responses from the company are reviewed by the
inspectors.
Non compliance to EMA inspection
Education
Inspection
Warning
Naming non complaint MAH- Public
Formal caution
Prosecution
Each inspection will result in an inspection report (IR)
prepared in accordance with an agreed format.
For multiple site inspections, an Inspection Overview (IO) is
prepared, addressing the major and critical findings
recorded for all sites.
in event of non compliance, following regulatory actions can
be taken:
Report
FDA Inspection
FDA inspections can occur only in US without prior notice
(previous inspection violative). In case an announcement is
made, it is not more than 5 days prior to the inspection.

FDA Form 482 (Notice of inspection) - to notify the
company about the inspection schedule after arrival.
FDA Form 483- to notify the company about the
inspectional significant observations.
FDA Form 486- warning letters will be issued to the
company in case of non-compliance.
Non compliance to FDA Inspection
After complete evaluation FDA sends the report to the
company, the reports are classified by FDA as:
Role of the Marketing Authorization Holders and Applicants
Always to be inspection-ready
To maintain and make available to the inspectors on
request, no later than 7 calendar days after the receipt of a
request.
The pharmacovigilance system master file as required.
To ensure sites selected for inspection agree to be
inspected before inspections..
MAH and applicant who have submitted new drug application
have responsibilities in relation to inspections, including but
not limited to the following:

Ensure that relevant staff involved in pharmacovigilance
activities or related activities are present and available
during the inspection for interviews or clarification of issues
identified.
Ensure that relevant pharmacovigilance data is accessible
from at least one point in the Union.
Ensure that if critical or significant findings are observed
during an inspection, appropriate and timely corrective
and preventative action plans are implemented.
Audits are carried out to be in preparation for inspection
from the regulatory authorities.
There is a significant differences between FDA & EMEA
inspections in context to regulatory variations but their
overall goals remain the same, that is safety of the
authorized medicinal products.

Introduction to GVP Modules
and GVP Module VI
Agenda
What are GVP modules
List of GVP modules
Module VI in detail
*Terminologies
*Structure and process
What are GVP Modules
Good pharmacovigilance practices (GVP) are the set of
measures drawn up to facilitate the performance of
pharmacovigilance in the European Union (EU).
GVP apply to marketing-authorization holders, the European
Medicines Agency and medicines regulatory authorities in
EU Member States.
They cover medicines authorized centrally via the Agency
as well as medicines authorized at national level.

GVP Modules (1/3)
The module numbers XI, XII, XIII and XIV stay void, as their
planned topics have been addressed by other guidance
documents on the Agency’s website.

Apart from Modules we also have Annexures:
GVP Module VI
GVP Module VI (1/2)
This Module of GVP addresses the collection, data
management and submission of individual reports of
suspected adverse reactions (serious and non-serious)
associated with medicinal products for human use
authorized in the European Union (EU).
The guidance does not address the collection,
management and submission of individual reports of
events or patterns of use, which do not result in suspected
adverse reactions (e.g. asymptomatic overdose, abuse,
misuse or medication error) and which are not required to
be submitted as individual case safety reports (ICSRs).
This information may however need to be collected and
presented in periodic safety update reports (PSURs) for the
interpretation of safety data or for the benefit risk
evaluation of medicinal products.

Terminologies (Definitions)
Adverse Reaction (1/3)
The use of a medicinal product within the terms of the
marketing authorization
The use outside the terms of the marketing authorization,
including overdose
Off-label use, misuse, abuse and medication errors.
Occupational exposure
Causality is relationship between a suspected medicinal
product and an adverse event.
An adverse reaction implies at least a reasonable possibility
of a causal relationship between a suspected medicinal
product and an adverse event.
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, it meets the definition of an adverse reaction.
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 reporters specifically state that
they believe the events to be unrelated or that a causal
relationship can be excluded.
An adverse reaction is a response to a medicinal product which
is noxious and unintended. This includes adverse reactions
which arise from:

Overdose, Off-label use and Misuse
Overdose: This refers to the 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. Clinical
judgement should always be applied.
Off-label use: This relates to situations where the medicinal
product is intentionally used (prescribed by physician) for a
medical purpose not in accordance with the terms of the
marketing authorization.
Misuse: This refers to situations where the medicinal product
is intentionally and inappropriately used not in accordance
with the terms of marketing authorization.
Abuse, Occupational exposure and Medication
error
Abuse: Persistent or sporadic, intentional excessive use of a
medicinal product, which is accompanied by harmful physical
or psychological effects.
Occupational exposure: This refers to the 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.
Medication error: This is an unintended failure in the drug
treatment process that leads to or has the potential to lead to
harm to the patient.

Medicinal Product
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.
Medicinal Product is characterized by any substance or
combination of substances:
Falsified medicinal product
its identity, including its packaging and labelling, its name
or its composition as regards any of the ingredients
including excipients and the strength of those ingredients
its source, including its manufacturer, its country of
manufacturing, its country of origin or its marketing
authorization holder (MAH); or
its history, including the records and documents relating to
the distribution channels used.
This relates to any medicinal product with a false
representation of:
Primary Source

Primary source of the information is the person who
reports the facts about an ICSR. Include all primary
sources if have multiple reporters including their
qualification.
In accordance with the ICH-E2D:
Healthcare professional is a medically-qualified person
such as a physician, dentist, pharmacist, nurse, coroner or
as otherwise specified by local regulations,
Consumer is a person who is not a healthcare professional
such as a patient, lawyer, friend, relative of a patient or
carer.
1.
2.
Medically confirmed reports (1/2)
A consumer may provide medical documentations (e.g.
laboratory or other test data) that support the occurrence
of a suspected adverse reaction and which indicate that
an identifiable healthcare professional suspects a causal
relationship between a medicinal product and the
reported adverse reaction.
A report may be notified by a medically qualified patient,
friend, relative or carer of the patient.
Where one or more suspected adverse reactions initially
reported by a consumer are subsequently confirmed by a
healthcare professional, the ICSR should be considered
medically confirmed. It should be updated at case level in
line with ICH-E2B(R2), or at adverse reaction level in
accordance with ICH-E2B(R3) for each subsequently
medically confirmed suspected adverse reaction.
The reported information is considered medically confirmed:

Seriousness
Death
Life-threatening
Requires inpatient or prolongation of hospitalization
Persistent or significant disability or incapacity
Congenital Anomaly/ Birth Defect
Medically significant event: Events that do not fall on above
criteria but if not paid attention may jeopardise the
patient’s health and can lead to the above circumstances
and the events that are lists in IME LIST.
As per ICH E2A, a serious adverse reaction corresponds to any
untoward medical occurrence that at any dose results in:

Structure and process
Collection of individual safety reports
Competent Authority (CA) and MAHs should collect and
collate all reports on the suspected adverse reactions.
PV system should be developed and designed to ensure:
the collected reports are authentic, legible, accurate,
consistent, verifiable and as complete as possible for their
clinical assessment.
reports of suspected adverse reactions to be validated in a
timely manner and exchanged between CA and MAHs within
the legal submission time frame.
1.
2.
Types of safety reports in the post-
authorization phase

Spontaneous Reports
A spontaneous report is an unsolicited communication by a
healthcare professional, or consumer to a CA, MAH or other
organization (e.g. regional pharmacovigilance center,
poison control center) that describes one or more
suspected adverse reactions in a patient who was given
one or more medicinal products. It does not derive from a
study or any organized data collection system.
Stimulated reporting which are still considered spontaneous
are (direct healthcare professional communication, press
publication, class action lawsuits) irrespective of medical
confirmation.
Literature Reports
The medical literature is a significant source of information
for the monitoring of the safety profile and of the risk-benefit
balance of medicinal products, particularly in relation to the
detection of new safety signals or emerging safety issues.
European Medicines Agency monitors selected medical
literature for reports of suspected adverse reactions to
medicinal products containing certain active substances
and enters into the EudraVigilance database relevant
information from selected medical literature.
Review, abstracts, meetings, draft manuscripts qualify for
being ICSR if have suspected adverse reactions.
If multiple medicinal products are mentioned in the
publication, only those which are identified by the
publication's author(s) as having at least a possible causal
relationship with the suspected adverse reaction should be
considered for literature review by the concerned MAHs.
One case for each identifiable patient.

Publication author is the primary source.
Searching should not be limited just to English.
Search should include Active substance and trade,
chemical names, metabolites, medication error, off-label
use, pregnancy, fatal, death, fatality etc.
If abstract does not have enough information; order full
article.
Literature articles do not qualify for being ICSR if other
company’s brand name or country where no MAH is held.
Other Nonmedical Source Reports
This includes report from lay press or other media.
It should be managed as a spontaneous report.
Internet or Digital Media (1/3)
MAH should regularly screen the internet or digital media,
under their management or responsibility, for potential
reports of suspected adverse reactions.
The frequency of the screening should allow for potential
valid ICSRs to be submitted to the competent authorities
within the appropriate regulatory submission time frames
based on the date the information was posted on the
internet site/digital medium.
MAH should consider utilizing their websites to facilitate the
collection of reports of suspected adverse reactions.

If a MAH becomes aware of a report of suspected adverse
reaction described in any non-company sponsored digital
medium, the report should be assessed to determine
whether it qualifies for submission as ICSR.
It should be handled as spontaneous reports. The same
submission time frames as for spontaneous reports should
be applied.
The identifiability of the reporter refers to the possibility of
verification of the existence of a real person based on the
information available e.g. an email address under a valid
format has been provided.
If the country of the primary source is missing, the country
where the information was received, or where the review
took place, should be used as the primary source country.
Solicited sources (1/2)
Clinical trials
Non-interventional studies
Registries
Post-approval named patient use programs
Other patient support and disease management programs
Surveys of patients or healthcare providers
Compassionate use or name patient use
Information gathering on efficacy or patient compliance
As per ICH E2D, Solicited reports are those derived from
organized data collection systems, which include:

Solicited reports should always be classified as study
reports.
Should have an appropriate causality assessment, to
consider whether they refer to Serious Adverse Reaction(s)
and therefore meet the criteria for reporting.
Protocol of non-interventional post-authorization studies
provides differently and does not require their systematic
collection.
Originating from compassionate use or named patient use
conducted in Member States where the active collection of
adverse events occurring in these programs is not required.
Exception include for the following which are considered as
spontaneous:
Validation of reports
Only valid ICSRs qualify for submissions.
Four minimum criteria are required for ICSRs validation.
One or more identifiable reporter: characterized by
parameters:
qualification (e.g. physician, pharmacist, other HCP, lawyer,
consumer or other non-HCP),
name, initials, or address (e.g. reporter’s organisation,
department, street, city, state or province, postcode, country,
email, phone number).
Local data protection laws might apply.

initials, date of birth, age, age group,
medical record number (from general practitioner,
specialist, hospital, or investigation),
gestation period, or
gender
One single identifiable patient: characterized by at least one
qualifying descriptors:
trade name or generic name of the drug,
Interacting substances or medicinal products should also
be considered suspected.
Disease, sign and symptoms, lab findings
One or more suspected substance/medicinal product:
One or more suspected adverse reaction:
Note:
If the primary source has made an explicit statement that a
causal relationship between the medicinal product and the
reported adverse event has been excluded and the notified CA
or MAH agrees with this assessment, the report does not qualify
as a valid ICSR since the minimum information for validation is
incomplete (there is no suspected adverse reaction).
The report also does not qualify as a valid ICSR if it is reported
that the patient experienced an unspecified adverse reaction
and there is no information on the type of adverse reaction.
An MAH is made aware that a patient was hospitalized or died,
without any further information. In this particular situation,
medical judgement should always be applied in deciding
whether the notified information is an adverse reaction or an
event. For example, a report of sudden death would usually
need to be considered as a case of suspected adverse
reaction and the valid ICSR should be submitted.

Follow-up Activity
The lack of any of the four elements means that the case is
considered incomplete and does not qualify for submission
as ICSR.
Competent authorities and MAH are expected to exercise due
diligence in following-up the case to collect the missing data
elements and follow-up activities should be documented.
Reports, for which the minimum information is incomplete,
should be recorded within the pharmacovigilance system for
use in on-going safety evaluation activities.
When the missing information has been obtained (including
for example when the medicinal product causal relationship
with the reported adverse event is no longer excluded), the
ICSR becomes valid for submission and the EU guidance
provided in VI.C.6.2.3.8. should be followed.
Follow-up methods should be tailored towards optimizing the
collection of missing information.
For suspected adverse reactions, it is necessary to obtain
supplementary detailed information significant for the
scientific evaluation of the cases.
This is particularly relevant for monitored events of special
interest, prospective reports of pregnancy (see VI.B.6.1. for
guidance on the management of pregnancy reports), cases
notifying the death of a patient, or cases reporting new risks
or changes in the known risks.
Patient’s age is important in order to be able to identify safety
issues occurring specifically in the paediatric or elderly
population. Reasonable efforts should be made to follow-up
on ICSRs where information on the patient’s age or age group
is initially not reported by the primary source.

A duplicate case refers to the same ICSR reported by
different senders, through different routes.
Detection and handling of duplicates by National
Competent Authorities (NCAs), MAHs and Sponsors of
clinical trials (Sponsors) is an important element of good
case management.
The presence of duplicates in any pharmacovigilance
system can create misleading signals and therefore impact
on the safety monitoring and potential regulatory actions.
For biological medicinal products, all appropriate measures
should be taken to clearly identify the names of the
products and their batch numbers.
Any attempt to obtain follow-up information should be
documented.
Duplicate cases(1/4)
Duplicate case detection:
Every newly received ICSR referring to an individual case
should be considered a potential duplicate and should be
checked thoroughly against the cases that are already
present in the database.

For pharmacovigilance systems, a simple table which
sorts the reports by age, sex, suspected/interacting
medicinal products and adverse reactions can be suitable
to detect similarities. Adding ‘country’ to this search can be
valuable, depending on the dataset.
Individual cases originating from clinical trials are usually
well-documented and duplicate detection can include
other criteria which will be more reliable, e.g. Research
centre ID and study details (EudraCT number, protocol
number).
Duplicate case confirmation:
Upon identification of potential duplicates, a manual
confirmation will always be necessary. A well documented
case, including a case narrative, is a prerequisite to
confirm if two cases are duplicates.
Population of the ‘Report duplicates’ section (ICH-E2B(R2)
data field ‘A.1.11’/ ICH-E2B(R3) data field ‘C.1.9.1’) with all
other reference numbers by which the case is known is a
particularly effective method of enabling detection and
confirmation of duplicates
Management of duplicates cases:
Duplicate cases are generally managed through a process
of merging two or more cases into one master case. This
process can consist of one of the following approaches:
The master case can either be based on one of the existing
cases, with information from the other subordinate
duplicate cases added unless the same, or more precise,
information is already present in the master case (this is
referred to in this document as “Allocation of a master
case”), or;

The master case can be created as a new case combining
the information from the subordinate duplicate cases (this
is referred to in this document as “Creation of a master
case”).
The master case should always contain all case reference
numbers from all subordinate duplicate cases, such that
they can be easily traced. The master case should reflect
the most accurate and up-to-date information available to
the organization.
Data Management (1/3)
Electronic data and paper records to be stored and should
be treated same as medical records with due respect and
confidentiality.
Patient and report confidentiality must be protected.
Electronic data storage should allow traceability (audit
trail) of all data entered or modified, including dates and
sources of received data, as well as dates and destinations
of transmitted data
To ensure pharmacovigilance data security and
confidentiality, strict control measures should be in place to
provide access to documents and to databases only to
authorized personnel.
Transmit ICSR between MAH and CA based on local data
privacy laws.
Reconciliation of data transfer with a third party.
Data received from the primary source should be treated in
an unbiased and unfiltered way and inferences as well as
imputations should be avoided during data entry or
electronic submission.

The reports should include the verbatim text as used by the
primary source or an accurate translation of it, the verbatim
must be coded appropriately, to ensure consistency, the
staff must be trained, there must be quality check at each
level and proficiency must be confirmed.
The data received via primary source must not be
corrupted.
A proper procedure must be placed to ensure duplicate
search are performed.
What is General Data Protection regulation? (1/2)
The General Data Protection Regulation ("GDPR") is a
regulation in EU law on data protection and privacy for all
individuals within the European Union (EU). It also addresses
the export of personal data outside the EU and EEA areas.
The GDPR aims primarily to give control to individuals over
their personal data.
The regulation applies to organizations/companies that
control or process personal data of EU & EEA residents with
or without a physical presence in the EU.
Effective date of GDPR: 25-May-2018
The GDPR considers obtaining data subject’s “consent”
(which must be freely given specifically informed and
unambiguous) before processing his/her data, as the
fundamental basis of data protection law.
Processing personal data is generally prohibited, unless:
It is expressly allowed by national law
Or data subject has consented to the processing.
*Personal data: are any information which are related to be an
identified or identifiable natural person.

Data Protection Officers is responsible for managing
compliance with GDPR.
In case of noncompliance with GDPR, company will be fined
up to 4% of annual global turnover or €20 Million
(whichever is greater).
Quality Management
CA and MAH should have a quality management system in
place to ensure compliance with the necessary quality
standards at every stage of case documentation, such as
data collection, data transfer, data management, data
coding, case validation, case evaluation, case follow-up,
ICSR submission and case archiving.
Stored data with initial and follow-up reports should be
verified by quality control procedures.
Clear written standard operating procedures should
guarantee that the roles and responsibilities and the
required tasks are clear to all parties involved and that
there is provision for proper control and, when needed,
change of the system.
Staff directly performing pharmacovigilance activities
should be appropriately trained in applicable
pharmacovigilance legislation and guidelines, additional
specific training like training on coding on events and drugs
for data entry staff must be provided.

Special situations: Use of a medicinal product
during Pregnancy
Reports, where the embryo or foetus may have been
exposed to medicinal products (either through maternal
exposure and/or if the suspected medicinal product was
taken by the father), should be followed-up in order to
collect information on the outcome of the pregnancy and
the development of the child after birth.
Individual cases with an abnormal outcome associated
with a medicinal product following exposure during
pregnancy are classified as serious reports:
reports of congenital anomalies or developmental delay, in
the foetus or the child,
reports of foetal death and spontaneous abortion, and
reports of suspected adverse reactions in the neonate that
are classified as serious.
When an active substance (or one of its metabolites) has a
long half-life, this should be taken into account when
assessing the possibility of exposure of the embryo through
the mother and/or the father if the medicinal product was
taken before conception.
In certain circumstances, reports of pregnancy exposure
with no suspected reactions may necessitate to be
submitted as ICSRs:
1.
2.
3.
This may be a condition of the MAH or stipulated in the risk
management plan; for example pregnancy exposure to medicinal
products contraindicated in pregnancy or medicinal products with a
special need for surveillance because of a high teratogenic potential
(e.g. thalidomide, isotretinoin).
A signal of a possible teratogen effect (e.g. through a cluster of
similar abnormal outcomes) should be notified immediately.
1.
2.

Following type of reports should not be submitted as ICSRs
since there is no suspected adverse reaction, but it should
however be collected and discussed in the periodic safety
update reports:
reports of induced termination of pregnancy without
information on congenital malformation,
reports of pregnancy exposure without outcome data, or
reports which have a normal outcome.
1.
2.
3.
Special situations: Use of a medicinal product
during Breastfeeding
Suspected adverse reactions which occur in infants following exposure
to a medicinal product from breast milk should be submitted in
accordance with the criteria outlined in GVP Module 6 section VI.B.7. and
in line with the guidance provided in GVP Module 6 section VI.C.6.2.3.1. for
the electronic submission of those ICSRs in the EU.
Special situations: Use of a medicinal product in a
paediatric or elderly population
The collection of safety information in the paediatric or elderly
population is important.
Certain diseases and illness are common to the age groups. E.g.
puberty gingivitis in teens, mumps and measles in children,
Diabetes Mellitus, hypertension, kidney and liver disorders very
common in elderly population.
Reasonable attempts should therefore be made to obtain and
submit the age or age group of the patient, in order to be able
to identify potential safety signals specific to a population.

Special situations: Reports of overdose, abuse,
misuse, medication error or occupational
exposure
Reports with no associated suspected adverse reaction
should not be submitted as ICSRs.
They should be recorded when becoming aware of them
and considered in the PSURs as applicable.
Special situations: Lack of therapeutic efficacy
Lack of therapeutic efficacy (LOE) reports are normally not
submitted as ICSRs unless associated with suspected
adverse reaction but are discussed in PSURs.
In certain circumstances, reports of LOE with no suspected
adverse reactions may require to be submitted within a 15-
day time frame:
Medicinal products used in critical conditions or for the
treatment of life-threatening diseases, vaccines,
contraceptives are examples of such cases.
This applies unless the reporter has specifically stated that
the outcome was due to disease progression and was not
related to the medicinal product.
Clinical judgement should be used when considering if
cases of lack of therapeutic efficacy qualify for submission
as ICSRs.
1.
2.
3.

Report nullification: Previously transmitted ICSR is
considered completely void (nullified), for example when
the whole case was found to be erroneous. The process of
the nullification of a case is by means of a notification by
the sender to the receiver that this is no longer a valid case.
However case must be retained in database for audit
purpose.
Report amendment: Already submitted report may need to
be amended for example when, after an internal review or
according to an expert opinion some items have been
corrected (such as adverse event/reaction terms,
seriousness, seriousness criteria or causality assessment)
but without receipt of new information that would warrant
submission of a follow-up report.
Null Flavors: The Null Flavors are a collection of codes from
Health level 7 (HL7). These codes support the management
of missing information.
For example: age of the patient is unknown: code UNK, e.g.
date of birth of the patient cannot be shared due to local
data protection laws: code MSK.
Null Flavor used in ICSRs are as :
Other concepts (1/2)

ICSR narrative writing
An ICSR narrative provides a full and clinically relevant,
chronological account of the progression of an event
experienced during or after the period following the intake
of suspect medicinal product(s)/study drug(s).
It is stand-alone “medical story” about the adverse
event(s).
Automation in narrative writing is a current trend that every
pharmaceutical industry is adopting to provide quality and
consistency within the narratives batch.
The tool which helps in creating automated narratives,
extracts relevant information for all the identified patients in
desired format/template.
Key element and sequence in non-clinical
narrative:

Key element and sequence in clinical narrative:
Submission of ICSRs (1/2)
Day 0:
It is the first day when a notified CA or MAH gets knowledge
of a valid ICSR, irrespective of whether the information is
received during a weekend or public holiday.
The timelines for submission are based on calendar days.
Timelines for EU submission:

Modalities for submission of ICSRs
ICSRs should be submitted electronically as structured data
with the use of controlled vocabularies for the relevant data
elements where applicable.
Regarding the content and format of electronic ICSRs, CA and
MAH should adhere to the following:
the ICH M1 Terminology - Medical Dictionary for Regulatory
Activities (MedDRA), which should be used at the lowest level
term (LLT) level in the ICSRs. Stakeholders should follow the
recommendations of the MedDRA Maintenance Support
Service Organization (MSSO) regarding the switch to a new
MedDRA version.
the latest version of the Guide for MedDRA Users MedDRA
Term Selection: Points to Consider
The guidelines applicable for the ICH-E2B formats:

MedDRA
MedDRA is a user-responsive terminology and is
maintained by MSSO (Maintenance and Support Services
Organization)
It is updated twice yearly, official updates
1 March X.0 release (Complex and simple changes)
1 September X.1 release (Simple changes only)
ICSRs are usually coded for data entry at the most
specific (LLT) level, and outputs of counts or cases are
usually provided at the PT level. The higher levels (HLT,
HLGT and SOC) as well as SMQ are used for searching and
for organization and subtotaling of outputs.
1.
2.

Key points to remember
GVP modules apply to MAHs, the EMA and medicines
regulatory authorities in EU Member States.
GVP Module VI addresses the collection, data management
and submission of ICSRs (serious and non-serious)
associated with medicinal products for human use
authorized in the EU.
An adverse reaction is a response to a medicinal product
which is noxious and unintended. It is characterized by the
fact that a causal relationship between a medicinal product
and an occurrence is suspected.
A serious adverse reaction corresponds to any untoward
medical occurrence that at any dose results in death, life-
threatening, requires inpatient or prolongation of
hospitalization, persistent or significant disability or
incapacity, congenital anomaly/ birth defect and medically
significant event.
Only valid ICSRs qualify for submissions and it has four
minimum criteria : identifiable reporter, identifiable patient,
one/more suspected substance/medicinal product and
one/more suspected adverse reaction.
Day 0 is the first day when a notified CA or MAH gets
knowledge of a valid ICSR.
Follow-up methods should be tailored towards optimizing
the collection of missing information and it should be
documented.
Serious and Serious Case which becomes non-serious
based on new follow-up information, should be submitted
to Health Authority (HA) as soon as possible, but in no case
later than 15 calendar days from day 0. Non serious should
be submitted to HA within 90 calendar days from day 0.

ICSRs are usually coded for data entry at the most specific
(LLT) level, and outputs of counts or cases are usually
provided at the PT level.
Every newly received ICSR referring to an individual case
should be considered a potential duplicate and should be
checked thoroughly against the cases that are already
present in the database.
A narrative is a brief summary of specific events
experienced by patients post intake of suspect drug.

ICSR
Introduction
Objective
Classification
Contents of ICSR
Scope of ICSR
Perspectives of ICSR
Submission of ICSR
Conclusion
References
Need of ICSR……..

It is standard for the exchange of adverse event or product
problem reports to public health, patient safety and
healthcare quality improvement organizations or regulatory
authorities.
The Individual Case Safety Report (ICSR) is a Health Level Seven
standard for the capture of the information needed to support
the reporting of adverse events, product problems or consumer
complaints associated with the use of FDA regulated products.
INTRODUCTION
After a drug is introduced into the market, when a patient received a
drug and experienced one or more adverse events, an adverse
event form is submitted.
The most common format for presentation of a case report are the
Medwatch form and the CIOMS 1 form.
This CIOMS 1 form is also known as individual case safety report (ICSR).
Definition:
OBJECTIVE:
The main objective of developing ICSR is to develop an
internationally acceptable reporting method where by
manufacturers could report post marketing adverse drug
reactions rapidly , efficiently and effectively to regulators.

It is an Implementation Guide for FDA Medical Device
Reporting.
This standard supports reporting for drugs, therapeutic
biologics, blood derivatives, devices and vaccines.
It was approved as an ANSI Standard in 2005.
It supports electronic medical device reporting (eMDR) for
the FDA Center for Devices and Radiological Health (CDRH).
CLASSIFICATION
HL 7 ICSR Release 1
HL 7 ICSR Release 2:
The ICSR Release 2 supports a wider variety of products including

HL 7 ICSR Release 3:
It provides support for adverse event reporting for all FDA
regulated products.
It is currently being balloted as an SDO Joint Initiative
between three standards development organizations CEN,
HL7 and ISO.
At present, ICSR Release 3 replaces HL7 ICSR Release 2
FDA does not recommend implementation of ICSR Release 2
because the content will be deprecated with ICSR Release 3.
CONTENTS OF ICSR:
CH E2A ensures that the ICSR contains a “case narrative”,
meaning a comprehensive and complete medical description
of the case.
This should include
Patient characteristics
Diagnosis
Therapy Details
Medical History
Narrative of Clinical events alongside the relevant outcome
Results of laboratory tests along with the normal
ranges
“any other information that refutes or confirms an adverse
reaction”
1.
2.
3.
4.
5.
6.
7.

Scope of ICSR:
This ICSR Implementation Guide was created by the HL7
Patient Safety Special Interest Group (PSSIG) as a companion
document for early adopters of the standard.
provides an overview of the standard data attributes.
submission of device adverse event and product problem
reports to the FDA Center for Devices and Radiological Health
(CDRH).
As it is important to discuss how the HL7 ICSR can be used to
support existing or emerging public health surveillance
messaging requirements, some discussions are included in this
guide.
A. HL7 ICSR Relationship to the US National Health Infrastructure
Initiative
B. HL7 ICSR Relationship to the Canadian Public Health
Surveillance Program
C. HL7 ICSR Relationship to ICH E2B Message Specification
A. HL7 ICSR Relationship to the US National Health
Infrastructure Initiative :
NHII is an initiative set forth to improve the effectiveness, efficiency and
overall quality of health and health care in the US.

The NHII will support a comprehensive knowledge-based
network of interoperable systems of clinical, public health,
and personal health information
It would improve decision-making by making health
information available when and where it is needed.
It encompasses the set of technologies, standards,
applications, systems, values, and laws that support all
facets of individual health, health care, and public health.
FDA’s role in NHII covers:
Regulation of health-related products
Monitoring and reporting on safety and adverse effects
Coordination of a clinically useful drug code
Some of the organizations which helps in achieving the aims
of NHII are
1. ONCHIT
It provides leadership for the development and nationwide
implementation of an NHII to improve the quality and efficiency
of health care and the ability of consumers to manage their
care and safety.
2. The Consolidated Health Informatics (CHI)
It is one of the Office of Management and Budget's (OMB)
CHI is a collaborative effort to adopt health information
interoperability standards, particularly health vocabulary and
messaging standards.
CHI adopted 20 uniform standards for electronic exchange of clinical
information to be used across the federal health enterprise.
1.
2.
3.

B. HL7 ICSR Relationship to the Canadian Public Health
Surveillance Program :
The Canadian Public Health Surveillance (PHS) Program will
accelerate the implementation of health surveillance systems in
each of Canada’s public health jurisdictions.
PHS solution components include
Functional Components:
1. Communicable Disease Case Management
2. Outbreak Management
3. Alerts Management
4. Immunization Management
Service Delivery
Immunization Registry
5. Inventory Management (Materials & Vaccine)
6. Work Management (Scheduling & allocation)
7. Terminology Registry
based on HL7 Common Terminology Services standards
8. Disease Registry
Perspectives for ICSR Reporting
The ICSR supports adverse event reporting between a
variety of public health and patient safety organizations,
and different parties may be involved in the reporting
process.
Since these parties can exchange information with each
other, or send reports directly to the public health or
regulatory agency, it is important to grasp the relationships
between senders, and the manner in which these
relationships appear in the ICSR specification.

The diagram provides an example of the ways in which
different reporting parties are involved in the ICSR
submission process:
Initial Reporter:
The person who first recognizes an event as an adverse
event or a product problem.
He could be a
a heath professional working in the context of a
user facility.
affected person
a relative of that person
another associated party such as a lawyer.
1.
2.
3.
4.

Initial reporter is captured as the author of investigation.
Information is captured within section of that specification
User Facility/Importer:
User facility is captured as the author of investigation.
Information is captured within section of that specification.
Information related to the initial reporter is captured in the context
of the primary case notification.
Manufacturer/Reprocessor:
Manufacturer is captured as the author of investigation
Information is captured within section of that
specification
Information related to the initial reporter is captured in the
context of the primary case notification.
Information related to the user facility or importer is
captured in the context of the secondary case notification.

Regulatory Agency:
It is the organization responsible for authorizing the
production, distribution and marketing of products, and
monitoring compliance and safety for their use
SUBMISSION OF ICSR:
All the individual case safety reports are to be submitted to
Food and drug administration (FDA) for examination of all
the adverse events .
ICSR’s are submitted in two formats.
Paper submission:
Two copies of descriptive portion of ICSR are to be mailed to
central document room(CDR) of FDA.

Electronic submission:
The only permissible format for the electronic submission
of ICSRs is the XML format.
XML requires specialized formatting using a standard
structure.
Since 2000, FDA has accepted ICSRs electronically.
Currently, FDA only accepts electronic submissions of
ISCRs in the XML format, prepared in accordance with
International Conference on Harmonisation-E2B (ICH E2B)

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