This document discusses pharmacovigilance, which involves monitoring the effects of pharmaceutical products after they have been licensed for use, especially in order to identify adverse effects early. It defines key terms like adverse events, adverse reactions, and signals. It describes the WHO program for international drug monitoring and India's national pharmacovigilance program. The pharmacovigilance process involves data collection and management, signal detection, risk assessment, benefit-risk assessment, risk communication, and audit. Various methods for data collection and signal detection are discussed.

1. Pharmacovigilance
Dr. Ashishkumar Baheti
MD Pharmacology

2. 2
Pharmacovigilan
ce
The etymological roots are:
pharmakon (Greek) means drug and
vigilare (Latin) means to keep watch.

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

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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 antihistaminics

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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

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Adverse Reaction
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

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Unexpected Adverse Reaction
An adverse reaction nature and severity of which is not
consistent with domestic labelling or market authorisation, or
expected from characteristics of drug action.

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Why Pharmacovigilance ?
• Limited value of animal experiments
• Clinical trials are limited in time and number of
patients
• Patients are selected
• Rare or delayed serious reactions are
likely to remain unnoticed

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Disasters
• Sulfanilamide in 1937
• Thalidomide in 1962
• Practolol in 1974
• Rofecoxib-Voluntary withdrawal (Sept
2004)

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Aims of the Pharmacovigilance
• Contribute to the regulatory assessment of benefit,
harm, effectiveness and risk of medicines,
encouraging their safe, rational and more
effective(including cost effective) use
• Improve patient care and safety in relation to use of
medicines and all medical and paramedical
interventions
• Improve public health and safety in relation to use
of medicines
• Promote understanding, education and clinical
training in pharmacovigilance and its effective
communication to the public

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WHO Programme for International Drug
Monitoring
WHO Drug Monitoring Programme was established in
1968
As of October 2008, 89 countries had joined the
WHO Drug Monitoring Programme.

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It consists of a network of the
1.National Centres,
2.WHO Headquarters and
3.Uppsala Monitoring Centre which is WHO
Collaborating Centre for International Drug
Monitoring, in Uppsala, Sweden.

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Functions
• Identification and analysis of new adverse reaction
signal
• Provision of the WHO database
• Information exchange between WHO and National
Centres mainly through Vigimed
• Publication of periodical newsletters, guidelines
and books
• Provision of training and consultancy support to
National Centres

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Contd..
• Annual meetings for representatives of National Centres
• Producing WHO Drug Dictionary and the WHO Adverse
Reaction Terminology
• Development of pharmacovigilance as a science

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Status of India
• India joined the WHO Programme in 1998
• The Central Drugs Standard Control
Organization(CDSCO) launched the National
Pharmacovigilance Programme in November 2004.
• Basic purpose of this programme is to collate,
analyze and archive adverse drug reaction data for
making regulatory decisions regarding drugs
marketed in India.

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National Pharmacovigilance Program
• The program has a three-tier structure with
1) 2 Zonal Centers
2) 5 Regional Centers
3) 26 peripheral centers and
• National Pharmacovigilance Advisory
Committee
• National Pharmacovigilance Center at
CDCSO

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Noteworthy Features of NPP
• Foster a culture of notification amongst
doctors, pharmacists and nurses.
• The reporting forms maintain patient
confidentiality
• Now even practicing doctors and pharmacists can establish
Peripheral Pharmacovigilance Centers and get involved in
pharmacovigilance

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Pharmacovigilance Process
1. Data collection & Data management
2. Signal detection
3. Risk assessment and quantification
4. Benefit/ Risk assessment
5. Actions to reduce risk or increase benefit
6. Communication of risks or interventions
7. Audit

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Data collection & Data management
1.Passive surveillance
a) Spontaneous reporting
b) Case series
c) Large linked administrative database
d) Electronic medical records
2.Intensified reporting
3.Active Surveillance
4.Comparative Observational Studies
5.Targeted Clinical Investigations
6.Descriptive studies

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1.Passive surveillance
a) Spontaneous reporting
• play a major role in the identification of safety
signals once a drug is marketed
• Is voluntary for health professionals in most
countries
E.g. UK Yellow Card Scheme,
• Most useful
1.Where reaction is unusual and unexpected
2.Where ADRs occur in close temporal relation with
start of treatment or increase in dose

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Contd..
• Provide important information on at-risk groups,
risk factors, and clinical features of known serious
adverse drug reactions.
• ADRs are less likely to be suspected if they have
insidious onset
• Underreporting is an important limitation; causes
are lack of awareness, time, report forms,
misconception that absolute confidence that the
medicine caused the event is needed for reporting
• Reporting rates cannot be used to reliably estimate
incidence rates

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Reports for regulatory authorities are in form of
• Expedited adverse drug reaction (ADR) reports
• Periodic Safety Update Reports (PSURs)

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

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c) Large linked administrative database
• Large linked health administrative databases, such
as Medicaid in the USA and the Ontario provincial
databases
• contain data on millions of subjects
• the completeness of details, such as diagnoses,
are questionable in many circumstances
• may not be representative of the whole population.

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d) Electronic medical record (EMR)
• Large number and detail of the variables are
available like use of tobacco products and
nonprescription drugs, symptoms and signs,
laboratory data and social circumstances etc.
• can be combined to generate new diagnoses or
adverse events,
• Hypotheses which are not restricted to existing
diagnoses, can be explored

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2.Intensified reporting
To encourage and facilitate reporting for new
products or for limited time periods methods used
are
- on-line reporting of adverse events -
systematic stimulation of reporting of adverse
events based on a pre-designed method

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3. Active monitoring
Drug event 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 at pre-specified
intervals to obtain outcome information.
• More detailed information can be collected
• Limitation - poor response rates

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Registries
• A registry is a list of patients presenting with the same
characteristic(s)
• 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

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4.Comparative Observational Studies
• Are key component in the 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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5.Targeted Clinical Investigations
• to evaluate the mechanism of action for the adverse reaction
• pharmacodynamic and pharmacokinetic studies
• to investigate potential drug-drug interactions and food-drug
interactions

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6. Descriptive studies
• These studies are primarily used to obtain the background rate
of outcome events
• and/or establish the prevalence of the use of drugs in specified
populations.

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Pharmacovigilance Process steps
• 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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Signal detection
Signal
• Reported information on a possible causal
relationship between an adverse event and a drug,
the relationship being unknown or incompletely
documented previously.
• Usually more than a single report is required to
generate a signal, depending upon the seriousness
of the event and the quality of the information

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Contd..
• describes the first alert of a problem with a drug
• cannot be regarded as definitive
• indicates the need for further enquiry or action
• The automated systems used to generate signal is
called as data mining

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Data mining
is the application of statistical techniques, e.g. predictive
modelling, clustering, link analysis, deviation detection and
disproportionality measures, to databases to generate signal.

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• Signal detection pattern may be affected by coding
systems and retrieval
• For coding adverse events and reactions Medical
dictionary MedDRA was developed
• Signal prioritization is needed as detailed
evaluation using all relevant data is complex and
resource intensive
• Potential impact of a safety issue on public health
is major determinant for prioritization

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Contd..
• SNIP criteria
Strong signals that are judged to be New, clinically Important,
and have potential for Prevention will be given priority for further
evaluation

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Aim of statistical aids
To provide the 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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Measures of
disproportionality
are the commonly used techniques to identify
ADEs. It was used to
• Identify an association between delay of withdrawal
bleeding during concomitant use of oral
contraceptives and itraconazole
• The association of pericarditis with practolol but not
with other b-blockers
• The association of captopril and other angiotensin
converting enzymes with cough

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Pharmacovigilance Process steps
• Data collection & Data management
• Signal detection
• Risk assessment and quantification
• Benefit/ Risk assessment and decision making
• Actions to reduce risk or increase benefit
• Communication of risks or interventions
• Audit

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Risk assessment and quantification
Evaluation of drug safety issue
1. Causality assessment
2. Identifying other possible cause
3. Assesing the risk to individual and public

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Pharmacovigilance Process steps
• Data collection & Data management
• Signal detection
• Risk assessment and quantification
• Benefit/ Risk assessment and decision making
• Actions to reduce risk or increase benefit
• Communication of risks or interventions
• Audit

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Benefit/ Risk assessment and decision making
• Benefit/ Risk assessment is continued throughout
life of a drug
• Guidelines to assess risk/ benefit differ from
country to country
E.g. Trovafloxacin was withdrawn from but in US
its use was initially restricted and monitored
• CIOMS has set working group to produce
guidelines on standardized Benefit/ Risk
assessment

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Key elements of Benefit/ Risk assessment
• 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

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Pharmacovigilance Process steps
• Data collection & Data management
• Signal detection
• Risk assessment and quantification
• Benefit/ Risk assessment and decision making
• Actions to reduce risk or increase benefit
• Communication of risks or interventions
• Audit

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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

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Communication
• To prevent the ADRs effective communication is essential
• Communications need to planned, if possible communication
team should be employed
• different but compatible messages may be essential for health
care professionals, patients, and the media
• The messages should be informative, targeted, clear, balanced

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Pharmacovigilance Process steps
• Data collection & Data management
• Signal detection
• Risk assessment and quantification
• Benefit/ Risk assessment and decision making
• Actions to reduce risk or increase benefit
• Communication of risks or interventions
• Audit

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Audit
• To evaluate the outcomes of the interventions
• To plan future activities

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Considerations for future
• Involve professional organizations of healthcare providers like
IMA, IPA.
• Address clinicians’ concerns
• Collect adverse drug reaction data involving drugs of alternative
medicine and their interactions with drugs of modern medicine.
• Consider including reports of “lack of efficacy”

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Contd..
• Environmental implications need to be addressed

54. THANK YOU!