BASIC ASPECTS ,TERMINOLOGIES

AND ESTABLISHMENT OF
PHARMACOVIGILANCE

SUBMITTED BY,
SYAMA.J.S
MPHARM
1ST YEAR
DPS CHERUVANDOOR
 PHARMACOVIGILANCE

• Pharmacovigilance (PV) is defined as the science and activities

relating to the detection, assessment, understanding and prevention
of adverse effects or any other drug-related problem.

• Pharmacovigilance (PV) Drug Safety

• Pharmakon -drug +Vigilare -to keep watch =PHARMACOVIGILANCE

 Overview
• The tragedy of thalidomides in 1960s compelled health agencies
and regulators worldwide to deliberate on drug safety issues.

• Thousands of babies were born without limbs because of exposure

to thalidomide consumed by the pregnant mothers for morning
sickness.

• In 1963 , the World Health Assembly adopted a resolution for

rapid dissemination of information on ADRs.

• Later WHO Piolet Research Project for International Drug

Monitoring in 1968.
• WHO initiated the project with cooperation of ten countries ,
which have their own pharmacovigilance systems

• These countries had well established national drug monitoring

centers receiving ADR reports from healthcare professionals.

• Received reports were analyzed locally and then forwarded to the

WHO database, which since 1978 has been maintained by the
WHO Collaborating Centers for International Drug Monitoring ,
located in Uppsala, Sweden.

• Thus the science of pharmacovigilance or drug safety emerged.

Gradually more countries joined the WHO program for
International Drug Monitoring (PIDM).
• The Uppsala Monitoring Center (UMC) supports the PIDM by
collecting, assessing and communicating information from
member countries national pharmacovigilance programs with
regards to the benefits, harms, effectiveness and risk of drugs.

• At present , more than 150 countries are members of PIDM.

• India joined the programme in 1998, with three monitoring

centers , but was not successful because of lack of manpower
and lack of funding.
 AIM OF PHARMACOVIGILANCE

• PATIENT CARE

To improve patient care & safety in relation to medicines & all

medical & para-medical interventions

• PUBLIC HEALTH

To improve public health & safety in relation to the use of

medicines

• RISK BENEFIT & ASSESSMENT

To contribute to the assessment of benefit, harm, effectiveness

and risk of medicines
• COMMUNICATION
To promote understanding, clinical training & effective
communication to health professionals & the public

• To promote rational and safe use of medicines

 RESPONSIBILITIES

• Timely collection of data ,recording and notification

• Appropriate assessments (data completeness , seriousness)

• Expedited and periodic reporting

• Creates appropriate structures for communication

 NEED OF PHARMACOVIGILANCE

HUMANITARIAN CONCERN

• Animal toxicology is often not a good predictor for

human effects .

• Evidence of safety from clinical trials is insufficient due to

some limitations

• LIMITATIONS (phase 1-3): limited size , narrow population

(age &sex specific), narrow indications (only specific disease),
short duration
2. SAFE USE OF MEDICINES
it has been suggested that ADRs may cause 5700 deaths per
year in UK
3.ADRs MAY CAUSE SUDDEN DEATH
4.PROMOTING RATIONAL USE OF MEDICINES
5.ENSURING PUBLIC CONFIDENCE
6.ETHICAL CONCERN
not reporting serious reaction is unethical
The Minimum Requirements for a functional
Pharmacovigilance System

• A National Pharmacovigilance Centre with designated staff (at

least one full time), stable basic funding, clear mandates, well
defined structures and roles and collaborating with the WHO
Programme for International Drug Monitoring

• The existence of a National spontaneous reporting system with

a national individual case safety report (ICSR) form i.e. ADR
reporting form
• A national database or system for collating and managing
ADR reports
• A national ADR or pharmacovigilance advisory committee
able to provide technical assistance on causality assessment,
risk assessment, risk management case investigation and
where necessary crisis management including crisis
communication
• Clear communication strategy for routine communication and
crises communication
What informations should be reported
• On ADRs occurring

– in the course of the use of a drug

– from drug overdose whether accidental or intentional

– from drug abuse / misuse / non-approved use

– from drug withdrawal

– in the infant of a nursing mother

– possibly as a result of exposure of the mother or the fetus

during pregnancy
• ANY INFORMATION

on an ADR or lack of efficacy connected with the use of a

medical device/ drug product

• even if no ADR has been observed,

– From drug overdose whether accidental or intentional
– From drug abuse / misuse / non-approved use
– From drug administration during pregnancy
 GOVERNING BODIES

• The pharmaceutical industry

• Regulatory authorities

• WHO collaborating centre for international drug monitoring

• CIOMS(Council for International Organization of Medical

Sciences )
 ORGANISATIONS INVOLVED IN
PHARMACOVIGILANCE
• FDA: The Food and Drug Administration (FDA or USFDA) is
an agency of the United States Department of Health and
Human Services, one of the United States federal executive
departments
• responsible for protecting and promoting public health
through the regulation and supervision of food safety, tobacco
products, dietary supplements, prescription and over-
thecounter pharmaceutical drugs (medications), vaccines,
biopharmaceuticals, blood transfusions, medical devices,
electromagnetic radiation emitting devices (ERED), veterinary
products, and cosmetics.
• EMEA: The European Medicines Agency is a decentralised
body of the European Union located in London

• MHLW: Ministry of Health, Labor and Welfare,Japan

• CDSCO: The government of India with the assistance of

world bank has initiated the National pharmacovigilance
programme.

The central drugs standard control organization (CDSCO) is

coordinating the country wide pharmacovigilance programme
under the aegis of Ministry of health and family welfare,
DGHS New delhi
• UPPASALA MONITORING CENTRE
Vigibase: The Uppasala monitoring centre(UMC, on behalf of
WHO) has over 3 million AE case reportes from over 75
countries.

• The data are supplied by national health authorities. Most of

the data are from the United states and supplied by the FDA.

• The UMC does not review or assess the individual cases put
into database, but it does pharmacovigilance analyses and
signaling
TERMINOLOGIES OF PHARMACOVIGILANCE
1.ADVERSE EVENT

Any untoward medical occurrence that may present during

treatment with a pharmaceutical product but which does not
necessarily have a causal relationship with this treatment.

2.ADVERSE DRUG REACTION (ADR)

A response which is noxious and unintended, and which occurs at

doses normally used in humans for the prophylaxis, diagnosis, or
therapy of disease, or for the modification of physiological
function. (WHO, 1972).
 3.ALLOPATHY

Non-traditional, western scientific therapy, usually using

synthesised ingredients, but may also contain a purified active
ingredient extracted from a plant or other natural source, usually
in opposition to the disease.

4.ATTRIBUTABLE RISK

Difference between the risk in an

exposed population (absolute risk) and

the risk in an unexposed population (reference risk).

• Attributable risk is the result of an absolute comparison between

outcome frequency measurements, such as incidence.
5.BIOLOGICAL PRODUCTS

Medical products prepared from biological material of human,

animal or microbiologic origin (such as blood products, vaccines,
insulin).

6.CASUAL RELATIONSHIP

A relationship between one phenomenon or event (A) and another

(B) in which A precedes and causes B. In pharmacovigilance; a
medicine causing an adverse reaction.
7.CASUALITY ASSESSMENT

The evaluation of the likelihood that a

medicine was the causative agent of an

observed adverse reaction. Causality assessment is usually made

according established algorithms.

8.CAVEAT DOCUMENT

The formal advisory warning accompanying data release from the

WHO Global ICSR Database: it specifies the conditions and

reservations applying to interpretations and use of the data.

9.CEM-FLOW

Software developed by UMC for collection and analysis of

data in Cohort Event Monitoring.

10.CLINICAL TRIAL

A systematic study on pharmaceutical products in human

subjects (including patients and other volunteers) in order to
discover or verify the effects of and/or identify any adverse
reaction to investigational products, and/or to study the
absorption, distribution, metabolism and excretion (ADME) of
the products with the objective of ascertaining their efficacy
and safety
11.COHORT EVENT MONITORING

Cohort Event Monitoring (CEM) is a prospective, observational

study of events that occur during the use of medicines, for
intensified follow-up of selected medicinal products phase.
Patients are monitored from the time they begin treatment, and

for a defined period of time.

12.COMPLIANCE

Faithful adherence by the patient to the prescriber’s instructions.

13.CONTROL GROUP
The comparison group in drug-trials not being given the
studied drug.
14.CO START
Coding Symbols for a Thesaurus of Adverse Reaction Terms
developed by USFDA . But recently COSTART was replaced
by MedDRA.
15.CRITICAL TERMS
Some of the terms in WHO-ART are marked as ‘Critical
Terms’. These terms either refer to or might be indicative of
serious disease states, and warrant special attention, because of
their possible association with the risk of serious illness which
may lead to more decisive action than reports on other terms.
 16.DATA MINING

• extract information from a data and transform it into an

understandable structure for further use

• it is practical machine learning tools &techniques with java

• the term data mining appeared around 1990.

• currently data mining and knowledge discovery are used

interchangeably

• A related term with essentially the same meaning is

‘pattern discovery’.
• In pharmacovigilance, the commonest application of data mining
is so called disproportionality analysis, for example using the
Information component (IC).
• Six tasks
a) anomaly detection –identification of unusual data &data errors
that require further investigations.
b) association rule learning-searching relationship between
variables
c) clustering-discovering groups that are in some way similar
d) classification-to apply to new data
e) regression-models the data with least error
f) summarization-compact representation of data
• Medical data mining-HITECH act(Health Information
Technology for Economic and Clinical Health act)

-by this data mining opportunities are maximized

a) Free open source data mining soft ware & applications

carrot 2

GATE

Orange

rapid miner

b) Commercial data mining software & application

1) clara bridge 2 ) oracle data mining

3) statistical data miner

17.DE - CHALLENGE
The withdrawal of a drug from a patient; the point at which the
continuity, reduction or disappearance of adverse effects may be
observed.
18.DISPROPORTIONALITY ANALYSIS
Screening of ICSR databases for reporting rates which are
higher than expected. For drugADR pairs, common measures of
disproportionality are the Proportional Reporting Ratio (PRR),
the Reporting Odds Ratio (ROR), The Information Component
(IC), and the Empirical Bayes Geometrical Mean (EBGM).
There are also disproportionality measures for drug-drug-ADR
triplets, such as Omega (Ω).
19.INFORMATION COMPONENT

The Information component (IC) measures the disproportionality

in the reporting of a drug- ADR pair in an ICSR database,
relative to the reporting expected based on the overall reporting
of the drug and the ADR. Positive IC values indicate higher
reporting than expected. The IC has also been implemented on
electronic health records, to detect interesting temporal
relationships between drug prescriptions and medical events.

20.INCIDENCE

Number of new cases of an outcome which develop over a

defined time period in a defined population at risk
21.INDIVIDUAL CASE SAFETY REPORT (ICSR)
A report that contains ‘information describing a suspected
adverse drug reaction related to the administration of one or
more medicinal products to an individual patient’.
22.MedDRA
MedDRA is the Medical Dictionary for Regulatory Activities.
WHO-ART, the WHO Adverse Reactions Terminology, is now
mapped to MedDRA
• International medical terminology dictionary -Originally
available in English &Japanese
• MedDRA is organized as System Organ Class(SOC).which is
divided into
a)High level group terms(HLGT)
b)High level terms(HLT)
c)Preferred terms(PT)
d)lower level terms(LLT)
• MedDRA is managed by MSSO(Maintenance and Support
Services Organization)

• MSSO releases new version in twice a year (march&

September)

• March release is the main ,contains changes at the HLT level

&above

• September release contains changes at the PT level

• Latest version(16.1) was updated on sept 2013

23.MEMBER COUNTRIES

Countries which comply with the criteria for, and have joined
the WHO Programme for International Drug Monitoring.

24.NATIONAL PHARMACOVIGILANCE CENTRES

Organisations recognised by

governments to represent their

country in the WHO Programme

(usually the drug regulatory agency). A single, governmentally

recognized centre (or integrated system) within a country with
the clinical and scientific expertise to collect, collate, analyse
and give advice on all information related to drug safety.
25.OMEGA(Ω)
A measure of disproportionate reporting for drug-drug-ADR
triplets in ICSR databases, designed to highlight potential
signals of drug- drug interactions. Just like the more
established disproportionality measures for drug-ADR pairs, Ω
is based on a contrast between the observed and expected
number of reports. A positive Ω indicates higher reporting than
expected

26.PANI-FLOW

Software developed by UMC for collection and analysis of

data in relation to vaccinations in a pandemic situation.
27.PERIODIC SAFETY UPDATE REPORT
A systematic review of the global safety data which became
available to the manufacturer of a marketed drug during a
specific time period. Produced in an internationally agreed
format.

28.PHARMACOEPIDEMIOLOGY

Study of the use and effects of drugs in large populations.

29.PHARMACOENVIRONMENTOLOGY

form of pharmacovigilance which deals specifically with those

pharmacological agents that have impact on the environment
via elimination through living organisms subsequent to
pharmacotherapy.
30.PREDISPOSING FACTORS

Any aspect of the patient’s history (other than the drug) which
might explain reported adverse events (genetic factors, diet,
alcohol consumption, disease history, polypharmacy or use of
herbal medicines, for example).
31.PRESCRIPTION EVENT MONITORING(PEM)

System created to monitor adverse drug events in a population.

Prescribers are requested to report all events, regardless of
whether they are suspected adverse events, for identified
patients receiving a specified drug. Also more accurately named

Cohort Event Monitoring.

32.PREVALENCE

Number of existing cases of an outcome in a defined population

at a given point in time.

33.RECORD LINKAGE

Method of assembling information contained in two or more

records, e.g. In different sets of medical charts, and in vital
records such as birth and death certificates. This makes it
possible to relate significant health events that are remote from
one another in time and place.

34.REFERENCE RISK

Risk in a population of unexposed persons; also called baseline

risk. Reference risk can be measured over time (incidence) or
at a given time (prevalence). The unexposed population refers
to a reference population, as closely comparable to the exposed
population as possible, apart from the exposure.
35.RELATIVE RISK

Ratio of the risk in an exposed population (absolute risk) and

the risk in an unexposed population (reference risk). Relative
risk is the result of a relative comparison between outcome
frequency measurements, e.g. incidences.
 36.SIGNAL

• reported information on a possible causal relationship which is

being unknown or incompletely documented previously.

• usually more than 1 report is required to generate a signal

• depending upon the seriousness of the event and the quality of

the information. The publication of a signal usually implies the
need for some kind of review or action.

• before signals are published they are first clinically assessed

by PV experts at UMC(Uppsala monitoring centre ,Sweden)
• there are 3types of signals

1.confirmed signals-causal relationship between the drug and

adverse event

2.refuted(false) signals-no causal relationship

3.unconfirmed signals-require further investigation

37.SPONTANEOUS REPORTING

System whereby case reports of adverse drug events are

voluntarily submitted from health professionals and
pharmaceutical manufacturers to the national regulatory
authority.
 38.VIGIBASE

• a unique collection of international drug safety data. Vigibase is the

name of the WHO ICSR data base .

• Its consists of reports of adverse reactions

• common uses-

• signal detection

• updating product safety update reports

• compare the reports

• WHO member countries have access to the collected data and

analyze . Vigibase comprises 8million reports in which 2 lack new
reports are added quarterly
 39.VIGI FLOW

• Vigi -Flow is a complete ICSR management system created and

maintained by the UMC.

• It is web-based and built to adhere to the ICH-E2B standard.

• It can be used as the

national database for

countries in the WHO

Programme as it incor

porates tools for report

analysis, and facilitates sending reports to Vigi-Base.

a) input-ICSR data can be manually entered into vigiflow with
support from the latest version of terminologies such WHO-ART
or MedDRA
b) handICSRs-it ling of is easy to communicate within the
vigiflow by adding a digital note to the ICSR.
- once a report is complete the first version of the ICSR is
considered to be finalized.
c) analysis-search& statistics module is part of vigiflow .the
results can be exported in different output formats.
d) communication-data can be sent to external contacts such as
companies or other regulatory agencies
• Technical information-requirements are web browser , internet
connection.
• information stored in vigiflow is only accessible by users
within the same country.
• There are downloadable pdf information sheets available here
40.VIGI-MED
Share point based conferencing facility, exclusive to member
countries of the WHO Programme for International Drug
Monitoring for fast communication of topical pharmacovigilance
issues
41.VIGI SEARCH
A search service for accessing ICSRs stored in the Vigi-Base
database offered by the UMC to national pharmacovigilance
centres and other third-party inquirers.
42.VIGI-MINE

A statistical tool within Vigi-Search with vast statistical

material calculated for all DrugADR pairs (combinations)
available in Vigi-Base. The main features include the
disproportionality measure (IC value) stratified in
different ways and useful filter capabilities.
43.VIGILYZE

during may & June 2013 vigisearch & vigimine were replaced
by this. Its a search and analysis tool that provide access to
vigibase.

44.WHO-ART

Terminology for coding clinical information in relation to drug

therapy. WHO-ART is maintained by UMC.