Pharmacovigilance

DR. VEENA B. KUPATI

 History
• Pharmacovigilance (PV) was officially introduced in December 1961 with the publication of a
letter (case report) in the Lancet by W. McBride, the Australian doctor who first suspected a
causal link between serious fetal deformities (phocomelia) and thalidomide, a drug used
during pregnancy: Thalidomide was used as an antiemetic and sedative agent in pregnant
women.

• In 1968, the World Health Organization (WHO) promoted the “Programme for International
Drug Monitoring”, a pilot project aimed to centralize world data on adverse drug reactions
(ADRs). In particular, the main aim of the “WHO Programme” was to identify the earliest
possible PV signals.

• The term PV was proposed in the mid-70s by a French group of pharmacologists and
toxicologists to define the activities promoting “The assessment of the risks of side effects
potentially associated with drug treatment”
Introduction
• Pharmakon: (in greek) drug
• Vigilare (in latin) to keep watch
• Pharmacovigilance is the science & activities relating to the detection ,
assessment, understanding and prevention of adverse effects (WHO
collaborating center for international drug monitoring)
• Pharmacovigilance (PV) also called as drug safety
Aim
• To improve patient care and safety
• To improve public health and safety
• To contribute to the assessment of benefit, harm ,effectiveness and risk of
medicines
• To promote education and clinical training
• To promote rational and safe use of medicines
Responsibility
• 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

• SAFE USE OF MEDICINES it has been suggested that ADRs may cause 5700 deaths per year in UK

• ADRs ARE EXPENSIVE

• PROMOTING RATIONAL USE OF MEDICINES

• ENSURING PUBLIC CONFIDENCE

• ETHICAL CONCERN not reporting is serious reaction is unethical

Governing bodies

• The pharmaceutical industry

• Regulatory authorities
• WHO collaborating center for international drug monitoring
• CIOMS (Council for International Organization of Medical Sciences )
Methods of Pharmacovigilance
1.Individual case safety reports
2.Clinical review of case reports
3.Cohort event monitoring
4.Longitudinal electronic patient records
5.Spontaneous reporting
6.Periodic Safety Update Reports (PSUR)
7.Expedited report
8.Record linkage
1.Individual case safety reports

• Like yellow card system of the Pharmacovigilance section of the U.K.

• Their strength in signaling causal associations depend on the skill and
experience of the reporter and the documentation and characteristics of the
event.
2.Clinical review of case reports
• The quality of reports is variable, large national and international organizations
collect hundreds of thousands of reports each year , every one of which can’t
possibly be reviewed by the available experts.
• Even if each report could be reviewed, important reporting patterns would be
missed.
• Computational have therefore been developed to help highlight the most urgent
problems .
3.Cohort event monitoring
• Cohort Event Monitoring (CEM) systems for intensified follow up of selected
medicinal products.
• The main limitations are its restriction to small subset of medicinal products , the
relatively small fraction of the population covered
4.Longitudinal electronic patient records
• It is extremely valuable but underused.
• They cover large populations, provide detailed information on both exposed and
unexposed patients.
• Information is extracted directly from the computer systems in which physicians
store patient’s data.
• Privacy protection for patients and physicians is of the utmost importance.
5.Spontaneous reporting
• The reporting might be directly to the company, or it could be to the regulatory authority.
• Main limitation is under reporting.
• However , their main purpose is not the quantification of the frequency, but identification
of signals.
• When becoming aware of a serious adverse drug reaction , health care providers,
pharmacies, pharmaceutical companies shall report to the health authority.
• Time frame of reporting, report within a specific time frame(ex:7days) upon knowing of
any serious ADR.
6.Periodic Safety Update Reports (PSUR)
• Pre marketing clinical trials may not be sufficient to reflect the product safety profile.
Therefore medically advanced countries impose the “post marketing drug safety
monitoring period ” on new drugs.
• License holders shall proactively collect post marketing safety data, prepare PSUR and
submit them to the health authority.
• According to the “regulation of medical products under safety monitoring", if
pharmaceutical companies fail to submit PSUR as required, then the health authority
may reassess the safety of the concerned product.
• The last PSUR should be submitted before the expiration of the drug safety monitoring
period.
• The “summary bridging report” provides summarized information of the PSURs
7.Expedited report
• If there has been spontaneous reporting of a suspected ADR to a pharmaceutical
company, there are legal obligations on the company to report serious reactions
within a specified time frame to the regulatory authority.
• Based on the results of drug safety assessment, license holders shall report to
the health authorities in an expedited manner
8.Record linkage
• Bring together a variety of patient records.
• A specific example is prescription event monitoring scheme.
• It is less expensive but time consuming method.
Pharmacovigilance inspection
1.Routine inspection
2.Targeted inspection
• Routine inspections
• To make sure that pharmaceutical companies have the ability in performing
Pharmacovigilance activities
• Targeted inspection
a) Inspections irrelevant to drug safety
• Companies that have not yet been inspected
• Companies that launch their first product
• Companies which are newly merged

b) inspections relevant to drug safety

• Companies that delay or fail to take their obligations on safety monitoring
• Companies that delay to submit or submit incomplete periodic safety update reports
• Companies that failed to report drug safety related issues (like drug withdrawal with out
reporting )
Adverse Drug Reaction
• Adverse event reporting –comprises 4 elements
1.an identifiable patient
2.an identifiable reporter
3.a suspect drug
4.a suspected adverse event
Types of ADR
• Non immunological
a) TYPE A (or) predictable
b) TYPE B (or) unpredictable

• Immunological
a) TYPE -I (Ig E mediated)
b) TYPE -II (cytotoxic)
c) TYPE -III (immune complex)
d) TYPE -IV (cell mediated)

• Miscellaneous
a) Jarisch - herxheimer reaction
b) Infectious mononucleosis
Non immunological
• TYPE A (or) predictable
• Side Effects
• Secondary Effects
• Toxic Effects
• Mutagenicity & carcinogenicity
• Drug Interactions
• Teratogenicity
• Non immunological Activation Of Effector Pathways
• Exacerbation Of Disease
• Metabolic Alterations
• Drug Induced Chromosomal Damage
• Effect On Spermatogenesis
Cont..
• TYPE B (or) unpredictable
• Intolerance
• Idiosyncrasy
Steps of ADR monitoring
• Identifying adverse drug reactions
• Assessing causality
• Documentation of ADR
• Reporting serious ADRs to PV centres /ADR regulatory authorities
Steps of Pharmacovigilance
• Step 1 is the collection of reports about the adverse effect and all adverse reactions of the
drugs. All adverse reactions, including serious and unexpected effects, are subjected to
expedited reporting.
• Step 2 involves receiving the cumulative reports regarding the safety of drugs and sending
those reports to all the regulatory authorities.
• Step 3 The process of determining the specific adverse effect associated with a specified drug
and then comparing this drug with another drug having a similar worse effect.
• Step 4 Management of adverse effects of the drugs. Receive information regarding the harmful
effects on patients or population and seek a method to minimize these effects.
NARANJO algorithm
• For assessing the causality
• Definite = ≥9
• Probable = 5-8
• Possible = 1-4
• Doubtful = ≤ 0
Hartwig and Seigels scale
• For assessing the severity
• Mild ADRs – are self limiting and do not contribute to prolongation of length
of hospital stay.
• Moderate ADRs – require therapeutic intervention or hospital admission or
prolonged hospital stay by at least one day.
• Severe ADRs – life threatening, requiring intensive medical care or produce
disability or lead to death.
Application of Pharmacovigilance
• In national drug policy
• In the regulation of medicines
• In clinical practice
• In disease control public health programs (problems are apparent in situations for
the treatment of tropical diseases)
Post marketing surveillance(PMS)
• PMS is the practice of monitoring the safety of a pharmaceutical drug or medical device
often it has been released on the market and is an important part of the science of
Pharmacovigilance.

• Since drugs are approved on the basis of clinical trials, which involve relatively small
numbers of people & do not have other medical conditions.

• Approaches are
• Spontaneous reporting database
• Prescription event monitoring
• Electronic health records
• Patient registries
Post Marketing Surveillance
• USES
• No fixed duration or patient population
• Starts immediately after marketing
• Report all ADRs
• Helps to detect rare ADRs
• PMS-consists of 3 systems
1.ADR collecting and reporting system
2.Reexamination system
3.Reevaluation system
Post Marketing Surveillance
• Sources
• Focus groups
• Customer surveys
• Customer complaints& warranty

• Claims
• Literature reviews
• Media

• Benefits
• Improvement of medical device quality
• Verification of risk analysis
• Detection of chronic complaints
• Performance in different user population
• Customer satisfaction
• Need of PMS
• To develop information about drug effects
• To find rare adverse events
• Assess to more patient data

• Methods of surveillance
• Controlled clinical trials
• Spontaneous recording
• Cohort studies
• Case control studies
• All adverse events occurring in a PMS should be submitted to UMC in the form of fact sheet.
Pharmacovigilance programme of India (PVPI)
• Officially started on 23 November 2004 at new Delhi
• Pharmaceutical industry in India is valued at 90,000crore and is growing at the rate of 12-14%
per annum
• Total export of pharma products is to the extent of 40,000crore.
• India is now being recognized as the “global pharmacy of generic drugs”
• India is also emerging rapidly as a hub of global clinical trials & destination for drug discovery
and development
• In a vast country like India with a population of over1.2 billion with vast ethnic variability,
different disease prevalence patterns, practice of different systems of medicines, different SES,
it is important to have robust Pharmacovigilance and drug safety monitoring programs.
• PVPI is under control of
• 1. CDSCO (Central Drugs Standard Control Organization)
• 2. Directorate general of health services
• 3. Indian pharmacopeia commission (Ghaziabad)

• The program is conducting by NCC (National Coordinating Centre) .

Goals & objectives
• Goal
• To ensure that the benefits of use of medicine outweighs the risks
• Objectives
1. To monitor ADRs
2. To create awareness among health care professionals about ADRs
3. To monitor benefit –risk profile of medicines
4. Generate independent ,evidence based recommendations
5. Support the CDSCO
6. Communicate findings with all stake holders
7.Create a national centre
• PVPI will be administered and monitored by the following committees
• 1. Steering committee
• 2. Strategic advisory committee

• Technical support by
• 1. Signal review panel
• 2. Core training panel
• 3. Quality review panel
Steering committee
• Chairman: Drugs controller general (India), New Delhi
• Members
1.Scientific Director , Indian pharmacopoeia commission , Ghaziabad
2. Head of Dept. of Pharmacology ,AIIMS
3. Nominee of director general ,ICMR
4. Assistant director general as representative of directorate general health services
5. Under secretary as representative of the ministry of health & family welfare
6. Nominee of vice chancellor of medical/pharmacy university
7. Nominee of the medical council of India
8. Nominee of the pharmacy council of India
• PVPI is a 3 layered structure consisting of
1. Peripheral
2. Regional
3. Zonal centres
Collaboration with WHO - UMC

• Long term objective of the PVPI is to establish a centre of excellence- for that
• Training of the staff at the PVPI NCC
• Usage of UMC (Uppsala Monitoring Centre)s vigiflow (for medicines), paniflow
(for vaccines)
• Access to vigibase
• Access to early information about safety hazards
Operational aspects
• Roles and responsibilities of different personnel in PVPI
• Centre management
• Processing and reporting of suspected ADRs
• Quality assurance in the program
• Regulatory decision making
• Communication among various stake holders
Risk management
• Ensure availability and management of funds
• Conduct frequent training and awareness
• Detect and respond to under reporting ADRs
• Quality review of filled ADR forms
• Proper supervision of the centres
• Feed back to the health care professionals
Programme communications
• A,B,C,D,E – Programme communications
• 1,2,3,4 – ADR reporting
Monitoring and evaluation
• Process indicators
• Number of ADR monitoring centres participating
• Number of personnel trained in a year
• Funds budgeted and spent
• Out come indicators
• Number of ADR reports received in year
• Number of ADR reports processed in year
• Number of ADR reports submitted to vigiflow
• Impact indicators
• Number of signals generated and confirmed
• Number of safety related alerts issued by CDSCO
WHO Pharmacovigilance program
• Started in 1978 - Known as WHO program for international drug monitoring, which is located in Uppsala,
Sweden.
• As of October 2013, 117 countries have joined
• Functions
1. Identification and analysis of new ADR signals from national centres & sent to the WHO ICSR database
2. provision of the WHO database as a reference source.
3. Information exchange between WHO UMC , National centres through vigimed
4. Publications, news letters, guidelines and books in the pharmacovigilance
5. Supplying tools like WHO drug dictionary and WHO adverse reaction terminology
6. Training to national centres
7. Maintaining of computer software(vigiflow)
8. Annual meetings
9. Research on Pharmacovigilance
Reporting trends
• Preferred report format is the ICH E2B
• But some members still use the old WHO format(INTDIS)
• ICSRs should be sent once every month but at least every quarterly
Timeline of reporting an ADR
• By sponsor to Licensing Authority – 14 calendar days
• Investigation to sponsor within 24 hours
• Investigation to Ethic Committee within 7 working days
Summary