1

• Pharmacovigilance (PV) Etymological roots : pharmakon (Greek) means

drug and vigilare (Latin) means to keep awake or alert, to keep watch

WHO Definition
Science, activities relating to detection, assessment, understanding and
prevention of adverse effects or any other drug related problems

Side Effect
Any unintended effect of a pharmaceutical product occurring at doses
normally used in man which is related to the pharmacological properties
of the drug e.g. sedation with anti histaminics

Adverse Event / Adverse Experience

Any untoward medical occurrence that may present during treatment
with a pharmaceutical product at the same time, does not necessarily
have a causal relationship with this treatment 2
Adverse Reaction (ADR)
A response to a drug which is noxious and unintended, and which occurs
at doses normally used in man for the prophylaxis, diagnosis, or therapy
of disease, or for the modification of physiological function

Active surveillance system

Collection of case safety information as continuous pre-organized
process

Spontaneous reporting
System whereby case reports of adverse drug events are voluntarily
submitted from health professionals and pharmaceutical manufacturers
to the national regulatory authority

Signal
Reported information on a possible causal relationship between an
adverse event and a drug, the relationship being unknown or
incompletely documented previously 3
 Adverse Event

Intensity Seriousness Expectation Causality

• Mild • Non Serious • Expected • Related

• Moderate • Serious • Unexpected • Un-related

• Severe

4
Poor knowledge of Pharmacology, adverse effects of drugs

Irrational use of drugs, poor prescribing patterns

Promotional activities by pharmaceutical company detailers

Lack of authentic sources of information

Liberal drug outlets and unhealthy pharmaceutical

practices

Liberal OTC and self medication

practices Ignorant, illiterate public 5

Pharmacological classification by Rawling and Thompson:

Type A (Augmented)

Type B (Bizarre)

Type C (Chronic)

Type D (Delayed)

Type E (End of use)

Type F (Failure)

6
Type A (Augmented) (dose related)
• Related to exaggerated pharmacological effects of drug
• Eg. Hypoglycemia with Insulin, hypotension by beta blockers, NSAID’s
induced gastric ulcers

Type B (Bizzarre)
• Unexpected, unpredictable, related to patient factors like genetic
predisposition
• Eg. Penicillin hypersensitivity, malignant hyperthermia

Type C (Chronic)
• Uncommon, irreversible, unexpected, unpredictable
• Due to long term use of drugs
• Eg. Hypothalamic pituitary adrenal axis suppression by
corticosteroids
Type D ( Delayed)
• Time related
• Eg. Teratogenesis, Carcinogenesis like clear cell cancer of
female reproductive tract 7
Type E (End of use/ withdrawal)
• Occurs due to sudden discontinuation of the drug after long term therapy
• Eg. Adrenocortical insufficiency due to sudden withdrawal of
corticosteroids, MI due to beta blocker withdrawal

Type F (Failure of therapy)

• Common, Dose related
• Often caused by drug interactions
• Eg. Inadequate dosage of an oral contraceptive particularly
when used
with specific enzyme inducers

• FDA monitors safety of human and veterinary drugs, biologics, medical

devices, foods, cosmetics, & other products

• Centre for Drug Evaluation and Research (CDER) regulates

prescription drugs
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• Encourage active surveillance

• Consider special activities and expertise required for the detection of

safety concerns related to vaccines, biologicals, herbal medicines,
biotechnology products and investigational drugs

• Improve signal detection systems by facilitating availability of ADR data

• Revisit definitions of terms used within field of PV including definitions of

specific ADRs to ensure reliability and universal understanding of data
obtained through ADR reporting systems

• Develop and implement ADR detection systems

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 PREVENTIO
N
• Improve access to reliable, unbiased drug information at all levels
of healthcare

• Improve access to safer and more effective medicines for

neglected diseases prevalent in developing communities

• Encourage awareness of drug safety and rational drug use among

health
professionals and the public

• Integrate PV activities into national drug policies e.g. standard treatment

guidelines, essential drugs lists and clinical practice

• Improve regulation and PV of traditional and herbal medicines

• response to drug which

Develop systems safety assess
problems
the impact of preventive actions taken10in
 COMMUNICATION

• Improve communication, collaboration between key partners in PV

• Principles of good communications practice in PV and drug

regulation should be encouraged

• Different solutions are likely to be developed in different countries

and
• regions, and the experience should be shared

• Develop better understanding of patients, their expectations of

medicines and their perception of risk, in order to facilitate programmes
that will inform public on benefit and harm associated with medicine

• Develop sustained, active relationships with media

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Post-marketing monitoring or PV or Phase IV clinical studies

• Provides information about long-term safety of drug

• Safety in extremes of age, special population like pregnant and nursing

women

• Information about Type B ADR’s, rare ADR’s

• In India, mandatory to submit Post Marketing Surveillance (PMS)

Report within 2 years of marketing drug

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• Limited value of animal experiments, Clinical trials

• ADRs constituting enormous burden on society

• Cost of drug related morbidity, mortality exceeding that of drug

itself

• 30-50% of ADRs are preventable

• Early detection and prevention can help make drug therapy lot safer

• Rare or delayed serious reactions are likely to remain unnoticed

13
• 1881  systemic recording of illnesses associated with
pharmacotherapy started much later and a book in this regard was
published by L. Lewin.
•
1937  Unexplained death of hundreds of children. Elixir of
sulfanilamide dissolved in diethylene glycol killing 107
• children n

1938  Stimulus for food and drug Act (drug safety) for stringent
actio regarding safety requirement and testing of a new drug before
• marketing.

• Thalidomide disaster in 1962

1968  WHO established a system for collecting reports of ADR

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NEWER CHALLENGES FACED TODAY

• Illegal sale of medicines and drugs of abuse over Internet

• Increasing self-medication practices
• Widespread manufacture and sale of counterfeit and sub standard
medicines
• Increasing use of traditional medicines outside confines of traditional
culture

Recently, PV concerns have been widened to include:

• Herbals
• Traditional and complementary medicines
• Blood products
• Biologicals
• Medical devices
• Vaccines
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Rational and safe use of medical drugs

Encourage their safe, rational, more effective, cost effective use

Educating and informing patients

Assessment and communication of risks and benefits of drug

Promote understanding, education and clinical training in PV and its

effective communication to the public

Improve patient and public healthcare and safety in relation to use

of medicines

Contribute to regulatory assessment of benefit, harm,

and risk of medicines
effectiveness 1
6
• Established in 1968

• As of October 2008, 89 countries had joined

• It consists of a network of the

i. National Centres
ii. WHO Headquarters
iii. Uppsala Monitoring Centre

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Identification and analysis of new adverse reaction signal

Provision of the WHO database

Information exchange between WHO and National Centres

mainly through Vigiflow

Publication of periodical newsletters, guidelines, books

Provision of training and consultancy support to National

Centres
18
• Located in Uppsala, Sweden, World Health Organisation Collaborating
Centre for International Drug Monitoring

• Principal function  manage international database of ADR reports

received from National Centres

• Works by collecting, assessing and communicating information from

member countries' national PV programs in regards to benefits, harm,
effectiveness and risks of drugs

• Annual meetings for representatives of National Centres

• Producing WHO Drug Dictionary and WHO Adverse Reaction

Terminology

19
1. Pharmacovigilance Specification

2. Pharmacovigilance Plan

3. Pharmacovigilance Methods

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Pre Clinical Studies
• Toxicity tests
• General pharmacology
• Effect of hepatic and renal dysfunction,
• Drug interactions, and
• Other toxicity-related information or data

Animal Tests
- Acute toxicity - Kinetics
- Carcinogenicity - Organ damage
- Mutagenicity - Species specificity
- Teratogenicity - Dose dependence

21
 Clinical Studies
• Adverse events (AEs) / Adverse drug reactions

• Identified and potential interactions, including food-drug and drug-

drug interactions

• Epidemiology of indication(s) and important adverse events

• Pharmacological class effects

• Limitations of the human safety database

22
 Investigator
immediately or
within 24 hours

Monitoring center
Death and immediately or
life-threatening, within 24 hours
Associated (by
Investigator)
Cases Sponsor’s Safety Officer
Immediately or
within 24 hours immediately or
to entry site within 24 hours
Global HQ
23
 Hospital
Regional
Centre

Health National
Patient Professional Centre

Manufacturer
• Relationship between the drug treatment and occurrence of an
adverse event

• Defined: structured and standardised assessment of individual

patients/case reports of the likelihood of involvement of suspected
drug in causing particular event in a given patientWHO assessment
scale

• Methods

Naranjo's scale European ABO system

Karch and Lasagna's scale Kramer scale
Bayesian Neural network Yale algorithm

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• Data collection & Data management

• Signal detection

• Risk assessment and quantification

• Benefit/ Risk assessment

• Actions to reduce risk or increase benefit

• Communication of risks or interventions

• Audit
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• Passive surveillance
a) Spontaneous reporting
b) Case series
c) Large linked administrative database
d) Electronic medical records

• Intensified reporting

• Active Surveillance

• Comparative Observational Studies

• Targeted Clinical Investigations

• Descriptive studies
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Spontaneous reporting

• Identification of safety signals once a drug is marketed

• Is voluntary for health professionals

• Most useful where reaction is unusual and unexpected

• And where ADRs occur in close temporal relation with start of

treatment or increase in dose

• Provide important information on at-risk groups, risk factors,

and
clinical features of known serious ADRs

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Reports for regulatory authorities are in form of

• Expedited adverse drug reaction (ADR) reports

• Periodic Safety Update Reports (PSURs)

• Underreporting is an important limitation

• Causes being lack of awareness of time, ill filled report forms,

misconception that the medicine caused the event

• Reporting rates cannot be used to reliably estimate incidence rates

29
Case series
• Provide evidence of association between drug and adverse event
• More useful for generating hypotheses than for verifying an association
between drug exposure and outcome
• Reports of events like SJS, Anaphylaxis should undergo detail and rapid
follow up

Large linked administrative database

• Eg. Medicaid in USA and Ontario provincial database
• Contain data on millions of subjects
• Completeness of details, such as diagnoses, are questionable in many
circumstances
• May not be representative of the whole population

Electronic medical record

• Large number and detail of variables are available like use of tobacco
products and nonprescription drugs, symptoms and signs,
• Can be combined to generate new diagnoses or adverse events,
• Hypotheses which are not restricted to existing diagnoses, can be
explored 30
• To encourage and facilitate reporting for new products, methods
used are
• Onine reporting of adverse events
• Systematic stimulation of reporting of adverse events based on a
pre-designed method

ACTIVE MONITORING
• Patients might be identified from electronic prescription data or
automated health insurance claims
• A follow-up questionnaire can then be sent to each prescribing
physician or patient to obtain outcome information
• More detailed information can be collected
• Limitation - poor response rates

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• A registry is a list of patients presenting with the same characteristics
• Used as information gathering and hypothesis generating tool
• Particularly on drug exposure during pregnancy and for orphan
drugs
• Can act as population basis for linkage studies

COMPARATIVE OBSERVATIONAL STUDIES

• Are key component in evaluation of adverse events
• Cross- sectional studies - primarily used to gather data for surveys or
for ecological analyses
• Case-control studies - used to investigate whether there is an
association between a drug (or drugs) and one specific rare
adverse event, as well as to identify risk factors for adverse events
• Cohort studies - incidence rates of adverse events in addition to the
relative risks of adverse events are calculated
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• Evaluate MOA for adverse reaction
• Pharmacodynamic and pharmacokinetic studies
• Investigate potential drug-drug interactions and food-drug interactions

DESCRIPTIVE STUDIES
• These are primarily used to obtain background rate of outcome events
• Establish prevalence of use of drugs in specified populations

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• Reported information on a possible causal relationship between an
adverse event and a drug

• Relationship being unknown or incompletely documented

previously

• Usually more than a single report is required to generate a signal

• Depending upon seriousness of event and quality of the

information

• Describes the first alert of a problem with a drug

• Cannot be regarded as definitive

• The automated
Indicates systems
the need used to
for further generate
enquiry signal is called as data
or action
mining 34
DATA MINING
Application of statistical techniques, e.g. predictive modeling,
clustering, link analysis, deviation detection and disproportionality
measures, to databases to generate signal

Signal Signal
Generation strengthening

Formulation of
Assessment of
hypothesis of
available data
association

Improved
Method of knowledge
highlighting about suspected
potential ADR and ADR and 35
safety issues of a indicates need
drug needing for early
further warning or
investigations intervention
SNIP criteria
Strong signals that are judged to be New, clinically Important, and
have potential for Prevention, be given priority for further evaluation

Methods of signal detection

• Spontaneous reporting system
• Hospital based surveillance system
• Prescription- event monitoring
• Case reports in literature
• Epidemiological studies

Aim of statistical aids

• To provide means of comparing the frequency of a medicine - event
combination
• With all other such combinations in the database under consideration
• With potential for early detection of signals of possible medicine -
event association
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Evaluation of drug safety issue

• Causality assessment
• Identifying other possible cause
• Assessing the risk to individual and public

• Benefit/ Risk assessment is continued throughout life of a drug

• Guidelines to assess risk/ benefit differ from country to country

Key elements
• Description of target disease, populations being treated, purpose
of intervention
• Degree of efficacy, presence of alternative therapy
• Type of risk and identification of risk factors
• Consideration of all benefits and risks by indication and population
37
Actions to reduce risk or increase benefit and Communication
• Contraindicate use of drug in specific group

• Reducing maximum authorized dose

• Contraindicating concomitant use of interacting drug

• Monitoring early warning signs

• Educating practitioners and consumers

• Withdrawal of drug

AUDIT
• To evaluate outcomes of the interventions

• To plan future activities

38
Other issues relevant include

• Substandard medicines

• Medication errors

• Lack of efficacy reports

• Use of medicines for indications that are not approved and for
which there is inadequate scientific basis

39
• 1986: ADR monitoring system consisting of 12 regional centres
each covering population of 50 million, was proposed for India

• 1989: 6 regional centers : Delhi, Mumbai, Calcutta,

Pondicherry, Lucknow, Chandigarh

• 1997: India joined WHO Monitoring Programme based in

Uppsala, Sweden

• 2004: The WHO sponsored and World Bank funded National

Pharmacovigilance Program (NPP) for India was made operational

• NPP was to be overseen by National Pharmacovigilance Advisory

Committee

40
• 2009: World bank funding ended and programme was temporarily
suspended

• Late 2009: workshop org by AIIMS, Dept. of Pharmacology and

CDCSO when a framework of new programme was formulated

• July, 2010: Recognizing the need for improved ADR monitoring in

the country, under the aegis of Health Ministry, a nation-wide
revised ADR monitoring programme was launched and named as
Pharmacovigilance Programme of India (PvPI)

41
• Provides a system to collect the data and use the inferences

• To recommended regulatory interventions, besides communicating

risks to healthcare professionals and public

• Indian Pharmacopoeia Commission (IPC) under the Ministry of Health

and Family Welfare has been functioning as the National Coordination
Centre (NCC) for PvPI since April 2011

• Medical colleges and hospitals are cornerstone of PvPI

• Under PvPI, ADRs are being identified and spontaneously reported by

the healthcare professionals of Adverse Drug Reaction Monitoring
Centres (AMC)

42
• Currently, 179 Medical Council of India approved teaching
hospitals and corporate hospitals have been identified as AMCs
across the country

• These AMCs are responsible for collecting adverse event as per

Standard Operating Procedure (SOP)

• Performing follow up if require for the completeness of ADR

reports

• Uploading these reports in net- based software used for ADR

reporting called as Vigiflow

• These drug safety information/Individual Case Safety Reports

(ICSRs) are collected in predesigned suspected ADR reporting forms

• Broadly consisting of 4 sections i.e., patient’s information, suspected

adverse reaction, suspected medication(s), and reporter’s
information
• Under PvPI, AMC plays a vital role in collection and follow-up of ADR
reports from healthcare professionals

• At present there are 400 AMCs under this programme and

categorized into four zones i.e., North, South, East and West

• Making this one of the largest Pharmacovigilance Programme in the

world

• PvPI have also extended its reach to other National Health

Programmes within country

• Integrating with Revised National Tuberculosis Control Program,

National AIDS Control Organization

• Has collaborations with Central Drugs Standard Control Organization

(CDSCO)
44
• Education and Training on PV at Regional Training Centres

• India, with a current population of 1.27 billion, is the fourth

largest producer of pharmaceuticals in the world

• With more than 6000 licensed manufacturers and over 60,000 branded
formulations in the market

• Over 5 years, has played a significant role in creating awareness among

healthcare professionals about reporting ADRs

• Having more than 1,49,000 ADRs reported till December 2015

• Currently, the contribution of India to the WHO global Individual Case

Safety Reports (ICSRs) database is 3%

• Its trying to create sufficient database on ADRs, awareness among

healthcare providers of government, corporate hospitals
45
Communications

• Website : websites of CDSCO (www.cdsco.nic.in) and NCC (www.

ipc.gov.in) are important tools for communication to the
stakeholders and public seeking specific information

• Media : communicate the findings in national newspapers, electronic

media, etc., on regular basis

• Newsletter: unique among healthcare professionals because it

focuses on the ADRs related information

• Scientific Journals

• Helpline Facility to Provide Assistance in ADR Reporting

• Android Mobile Application for Adverse Drug Reaction Reporting

46
• Co-ordination among clinician, pharmacist, and nurse appears vital in
contributing each of their respective expertise and experience to
promote the rational use of medicines

• The reason for poor reporting may also include financial incentives,
ignorance (only serious ADRs are to be reported), apprehension of
reporting serious ADRs, and lack of time or over load

• In year 2013, India’s contribution to WHO–UMC’s global drug

safety
database was 2%

• India was 7th in position among top 10 counties contributing

to global drug safety database

• Awareness about the ADR reporting among the healthcare providers

can improve the rate of reporting across the country
47
• Wide misconception that ‘natural’ means ‘safe’

• There are examples of traditional and herbal medicines being

adulterated or contaminated

• With allopathic medicines, chemicals such as corticosteroids, non-

steroidal anti-inflammatory agents and heavy metals

• Self-medication further aggravates the risk to patients

• When used in conjunction with other medicines there is potential of

serious adverse drug interactions

• These products should be governed by standards of safety, quality and

efficacy that are equivalent to those required for other
pharmaceutical products
48
• New vaccines for pandemic diseases such as HIV/AIDS and malaria are
in the later phases of development

• Vaccines and biologicals require modified systems of safety monitoring

often administered to healthy children, particularly used within a
national immunization programme

• The skills and infrastructure to deal with genuine adverse events are
essential in preventing or managing misplaced fear

• Caused by false or unproven signals from patients and health workers

that might adversely affect immunization cover

49
• Eg. concerns about safety of whole-cell Pertussis resulted in dramatic
reductions in vaccines coverage and a resurgence of Pertussis in
many countries

• Contamination of blood and blood products by infectious organisms

such as HIV and hepatitis B

• Quality of screening and sterilization procedures and appropriate

selection of donors are linked to the risks of contamination

• Such safety issues related to the use of plasma-derived medicinal

products fall under PV programmes

50
• Drug safety monitoring is an essential element for the effective use of
medicines and for high quality medical care
• PV is a clinical discipline in its own right - one that contributes to an ethos
of safety and serves as an indicator of standards of clinical care practised
within a country
• 3 approaches that might serve to increase awareness and interest in drug
safety among clinicians, and to address research issues are
• Education, training and access to reliable information
• Health professionals are more likely to identify and report important
ADRs if they have confidence in their ability to diagnose, manage and
prevent such reactions
• National PV centres and training institutions play a central role in this by
encouraging inclusion of the principles and methods of PV
• And the study of iatrogenic disease at UG and PG levels in schools of
medicine, pharmacy and nursing

51
• For all medicines there is a trade-off between benefits and the potential for harm

• To minimize the harm, it is necessary that medicines of good quality, safety and
efficacy are used rationally, and that the expectations and concerns of the patient
are taken into account when therapeutic decisions are made

• The discipline of PV has developed considerably since the 1972 WHO technical
report, and it remains a dynamic clinical and scientific discipline

• It has been essential to meet the challenges of the increasing range and potency of
medicines (including vaccines), which carry with them an inevitable and sometimes
unpredictable potential for harm

• When adverse effects and toxicity appear - particularly when previously unknown
in association with the medicine - it is essential that they should be analysed and
communicated effectively to an audience that has the knowledge to interpret the
information 52
• This is the role of PV. Much has already been achieved

• PV activities are expanding around the world

• This is reflected in the increasing number of national PV centres that

have been established in recent years

• There are still many countries where no formal systems for PV are in
place

• To ensure that the existing centres are effective, their impact on

public health and health costs should be measurable and the benefits
demonstrable

• Only then will widespread support and long term sustainability of PV

centres be assured
53
The following is a summary of some of the serious challenges facing PV
programmes in the next ten years

• Globalization

• Web-based sales and information

• Broader safety concerns

• Public health versus pharmaceutical industry economic growth

• Attitudes and perceptions to benefit and harm

54
• Very concept of detection of an ADR can jeopardize their economics

• Should realize that ADR monitoring can be a source of revenue

generation if a new indication is found for the drug

• Can be tackled by giving conditional clearance for marketing

of a new
drug

• Enforcing strict drug regulations

• So that Fraudulent and counterfeit drugs do not find a way

into the
market 55
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