Pharmacovigilance_ Dr Ruchi Kushwaha.pptx

A Worldwide Master Key for Drug Safety
Monitoring
Dr Ruchi Kushwaha
Hospital Administrator

“Dying from a disease is sometimes unavoidable; but dying from
an adverse drug reaction is unacceptable.”
-Dr. Vladimir Lepakhin
Geneva 2005

Introduction
The etymological roots for the word “pharmacovigilance” are:
• Pharmakon (Greek) = medicinal substance, and
• Vigilia (Latin) = to keep watch
“The pharmacological science relating to the detection, assessment,
understanding and prevention of adverse effects, particularly long-
term and short-term adverse effects of medicines.”
-WHO, 2002

Introduction
“Process and science of monitoring the safety of medicines and
taking action to reduce the risks and increase the benefits of
medicines”.
-The European Commission
Pharmacovigilance is an important and integral part of clinical research
Both, safety of clinical trials and post-marketing pharmacovigilance are
critical throughout the product lifecycle
PV activities include: collecting and managing data on the safety of
medicines, looking at individual case reports to detect new “signals”, pro-
active risk management to minimize any potential risk associated with the
use of medicines, communicating and informing stakeholders and patients

Drug Safety – some definitions
Adverse event/adverse experience (AE)-
Any untoward medical occurrence that may occur during treatment with a
pharmaceutical product but which does not necessarily have a causal
relationship with this treatment
Undesirable signs & symptoms
Disease or accidents
Abnormal lab finding ( leading to dose reduction / discontinuation / intervention )
Side effect - Any unintended effect of a pharmaceutical product occurring at doses
normally used in man, which is related to the pharmacological proprieties of the drug
Adverse drug 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 modification of physiological function – causal role is
suspected

SAE (Serious Adverse Event) - an AE or ADR that is associated with
Death
Life threatening
Results in hospitalization /Prolongs existing hospitalization
Persistent or significant disability or incapacity
Congenital anomaly or birth defect
Medically significant
SUSAR (Serious, unexpected, suspected adverse reaction)
Serious
Not included in Product Core Safety Data Sheet
Suspected link to the drug

In the context of Pharmaceutical Industry -
Regulatory Agencies expects and mandates ADR / Safety data / SIGNALS
– solicited / active reporting during drug development in the form of :
1) ICSR (Individual Case Study Report)
2) PSUR (Periodic Safety Update Report)
3) DSUR (Development Safety Update Report)

Origin of Pharmacovigilance
A new breakthrough in this field only happened after an episode occurring
in 1937; in that year, Sulfanilamide (Prontosil), used since 1932 for
treatment of streptococcal infections, was launched as a syrup, containing
diethyleneglycol as solvent
It was responsible for the death of 105 individuals (34 children and 71
adults) and diethyleneglycol was incriminated
This tragedy caused the American Congress to approve in 1938 the Food
Drug and Cosmetic Act, under which pharmaceutical product
manufacturers would have to show scientific evidences of the safety of the
drugs before releasing them for sale

Thalidomide Tragedy
The thalidomide tragedy is a milestone in the origin and development of
pharmacovigilance
Thalidomide was introduce in 1957 and widely prescribed as an allegedly
harmless treatment for morning sickness and nausea
It was tested in approximately 300 patients without toxicity but was soon
linked to a congenital abnormality phocomelia, which caused severe birth
defects in children of women who had been prescribed this medicine
during Pregnancy
In 1962, after reports of numerous cases of phocomelia, it was
discontinued In the same year, the Kefauver-Harris amendment was
approved, requiring scientific evidences of efficacy and safety before drug
tests in humans

Origin of Pharmacovigilance
As a means of pooling existing data on ADRs, WHO’s Programme for
International Drug Monitoring was started in 1968
Initially a pilot project in 10 countries with established national reporting
systems for ADRs, the network has since expanded significantly as more
countries worldwide developed national pharmacovigilance centers for the
recording of ADRs
Currently, 86 countries participate in the programme, which is coordinated
by WHO together with its collaborating centre in Uppsala, Sweden
The collaborating center is responsible for maintaining the global ADR
database, ‘Vigibase’
At present the database contains more than four million ADR reports

Why Pharmacovigilance?
Humanitarian concern
ADR are expensive
Promoting rational use of medicines and adherence
Ensuring public confidence
Ethics- to know of something that is harmful to another person who does
not know, and not telling, is unethical

Objectives of Pharmacovigilance
To improve patient care and safety in relation to the use of medicines and
all medical and paramedical interventions
To improve public health and safety in relation to the use of medicines
To detect problems related to the use of medicines and communicate the
findings in a timely manner
To contribute to the assessment of benefit, harm, effectiveness and risk of
medicines leading to the prevention of harm and maximization of benefit
To encourage the safe, rational and more effective (including cost-
effective) use of medicines
To promote understanding, education and clinical training in
pharmacovigilance and its effective communication to the public

Benefits of Pharmacovigilance
Prevention of drug related morbidity & mortality
Huge saving in healthcare costs
Better patient compliance
Greater understanding of drug induced disorders
Early signals/ warnings to potentially serious ADRs
Greater awareness of agents that commonly cause drug induced disorders
Better patient care

The WHO Programme for International
Drug Monitoring (PIDM)
In 1968, during the 16th World Assembly the 16.36 resolution called for “a
systematic collection of information on serious adverse drug reactions
during the development and particularly after medicines have been made
available for public use”.
This led to the formation of the WHO Programme for International Drug
Monitoring (PIDM)
WHO promotes PV at country level
Initially the WHO PIDM members consisted of 10 countries
Currently, 136 countries have joined the WHO PIDM, and in addition 29
associate members are awaiting full membership

Dark Blue: Full member
Light Blue: Associate member
White: Non-member

(PIDM)
WHO PIDM Member States submit reports of adverse reactions
associated with medicinal products, known as Individual Case Safety
Reports (ICSRs) to the WHO global database, VigiBaseTM
VigiBase is managed and maintained by the WHO Collaborating Centre
for International Drug Monitoring, known as the Uppsala Monitoring
Centre (UMC)
In October 2014, there were over 10 million reports of adverse reactions in
VigiBase
Data in VigiBase are recorded in a structured and comprehensive way to
allow the detection of potential medicinal safety hazards
In April 2015, the World Health Organization (WHO)
launched VigiAccessTM
VigiAccess is a new web application that will allow anyone to access
information and encourage the reporting of adverse effects from medicinal
products

Three-part Network of PIDM
The programme consists of a National pharmacovigilance centres from
WHO member countries are responsible for case reports sent to the WHO
ICSR database (managed by the Uppsala Monitoring Centre (UMC) in
Sweden)
1) UMC oversees the WHO programme operations, including:
1) Collecting, assessing and communicating information from member
countries about the benefits, harm, effectiveness and risks of drugs
2) Collaborating with member countries in the development and practice
of pharmacovigilance
3) Alerting NRAs of member countries about potential drug safety
problems via the WHO signal process
2) WHO headquarters in Geneva, Switzerland is responsible for policy
issues

Uppsala Monitoring Centre
an independent
not-for-profit foundation
a centre for international scientific research, based in Sweden – closely
associated with WHO, since 1978

The UMC Vigis...
VigiBase
• The WHO ICSR database
VigiSearch
• A web based tool to search VigiBase data
VigiFlow
• A separate tool for National Centres to manage their ICSRs
• Simplifies the process of sending ICSRs to VigiBase
• Can be used by both national authorities and companies for
management of their own reports

The Minimum Requirements for a
functional Pharmacovigilance System
1) A National Pharmacovigilance Centre with designated staff (at least one
fulltime), stable basic funding, clear mandates, well defined structures
and roles and collaborating with the WHO Programme for International
Drug Monitoring
2) The existence of a National spontaneous reporting system with a
national individual case safety report (ICSR) form i.e. ADR reporting form
3) A national data base or system for collating and managing ADR reports
4) 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
5) Clear communication strategy for routine communication and crises
communication

Need of Pharmacovigilance in India
In the past, India’s regulatory agencies and drug companies based their
safety assessments on experiences derived from long-term drug use in the
Western markets and there was no real urgency for the government to
establish a strong pharmacovigilance system of its own
In recent years, however, the lag between when a drug is placed in the
market and its subsequent availability in India has decreased considerably
so that the much needed longer-term safety data is no longer available
In addition, India-based drug companies have increased their capacity to
develop and launch new drugs through their own research efforts and this
has heightened the importance of developing adequate internal
pharmacovigilance standards to detect adverse drug events

Need of Pharmacovigilance in India
India is a vast country and there is a surfeit of drug brands—India is now
the fourth largest producer of pharmaceuticals in the world with more than
6,000 licensed drug manufacturers and over 60,000 branded formulations
It is also emerging as a hub for clinical trials
Many new drugs are being introduced in the country, so there is an
immense need to improve the pharmacovigilance system to protect the
Indian population from potential harm that may be caused by some of the
new drugs

Pharmacovigilance in India
The origin of pharmacovigilance in India goes back to 1986, when a formal
adverse drug reaction (ADR) monitoring system consisting of 12 regional
centres, each covering a population of 50 million, was proposed for India
In 1997, India joined the WHO Adverse Drug Reaction Monitoring
Programme based in Uppsala, Sweden
3 centres viz, AIIMS, KEM & AMU
In 2005, The Ministry of Health and Family Welfare in India initiated the
National Pharmacovigilance Program (NPP), coordinated by the Central
Drugs Standard Control Organization (CDSCO)
Programme was started with 2 zonal, 5 regional and 24 peripheral centres

Pharmacovigilance in India
Two zonal centers-the South-West zonal centre (located in the Department
of Clinical Pharmacology, Seth GS Medical College and KEM Hospital,
Mumbai) and
The North- East zonal centre (located in the Department of Pharmacology,
AIIMS, New Delhi), were to collate information from all over the country
and send it to the Committee as well as to the Uppsala monitoring centre
in Sweden
Three regional centers would report to the Mumbai center and two to the
New Delhi one
Each regional center in turn would have several peripheral centers
reporting to it
Presently there are 26 peripheral centers

E
Regional
N
Regional
W
Regional
W
Regional
NE
Zonal
SW
Zonal
National
PVig
Center

The Pharmacovigilance Program of India
(PvPI)
The Pharmacovigilance Program of India (PvPI) was launched with a
broad objective to safe guard the health of 1.27 billion people of India
Adverse drug Reactions (ADRs) are reported from all over the country to
NCC-PvPI, which also work in collaboration with the global ADR
monitoring centre (WHO-UMC), Sweden to contribute in the global ADRs
data base
NCC-PvPI monitors the ADRs among Indian population and helps the
regulatory authority of India (CDSCO) in taking decision for safe use of
medicines

The Central Drugs Standard Control Organization (CDSCO), Directorate
General of Health Services under the aegis of Ministry of Health & Family
Welfare, Government of India in association with Indian Pharmacopeia
commission, Ghaziabad is initiating a nation-wide Pharmacovigilance
Programme for protecting the health of the patients by promising drug
safety
The Pharmacovigilance Programme of India (PvPI) was started by the
Government of India on 14th July 2010 with the All India Institute of
Medical Sciences (AIIMS), New Delhi as the National Coordination Centre
for monitoring Adverse Drug
The Programme shall be coordinated by the Indian Pharmacopeia
commission, Ghaziabad as a National Coordinating Centre (NCC)

The centre will operate under the supervision of a Steering Committee
In the year 2010, 22 ADR monitoring centres including AIIMS, New Delhi
was set up under this Programme
To safeguard implementation of this programme in a more effective way,
the National Coordination Centre was shifted from the All India Institute of
Medical Sciences (AIIMS), New Delhi to the Indian Pharmacopoeia
Commission, Ghaziabad, Uttar Pradesh on 15th April 2011

PvPI
Mission:
Safeguard the health of the Indian population by ensuring that the benefits
of use of medicine outweigh the risks associated with its use
Vision:
To improve patient safety and welfare in Indian population by monitoring the
drug safety and thereby reducing the risk associated with use of medicines.

Objectives of PvPI
To create a nation-wide system for patient safety reporting
To identify and analyze the new signal (ADR) from the reported cases
To analyses the benefit - risk ratio of marketed medications
To generate the evidence based information on safety of medicines
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 emerge as a national center of excellence for pharmacovigilance activities
To collaborate with other national centers for the exchange of information and
data management
To provide training and consultancy support to other national pharmacovigilance
centers located across globe

Implementation of PvPI
IPC assumed the need for establishing local hospital based centres across
the nation for the better patient safety
It was significant to monitor both the known and previously unknown side
effects of medicines in order to determine any new information available in
relation to their safety profile
In an enormous country like India with a population of over 1.2 billion and
with vast ethnic variability, different disease prevalence patterns, practice
of different systems of medicines, different socioeconomic status, it was
imperative to have a standardized and robust pharmacovigilance and drug
safety monitoring programme for the nation

PvPI: Short term goals
To develop and implement pharmacovigilance 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

PvPI: Long term goals
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

Pharmacovigilance Methods
Passive surveillance:
Encompasses all spontaneous AEFI reporting
From immunisation service providers / hospitals / patients
Up to next levels: state/territory then national (TGA) and then global
Active surveillance:
Primarily used for characterization of the AEFI profile, rates and risk factors
Logistical and resource constraints limit wide application
Only for selected AEFI at selected institutions (sentinel) sites
Can also be carried out in the community setting (e.g. cohort event monitoring)

Committees under NCC
Steering Committee
Working Group
Quality Review Panel
Signal Review Panel
Core Training Panel

Communication under PvPI
Uppsala Monitoring Centre,
Sweden
National Coordination Centre
(NCC), IPC, Ghaziabad
Healthcare
Professionals
ADRs Monitoring
Centre
CDSCO
Headquarter,
New Delhi
CDSCO Zonal Offices
South Zone, Chennai
West Zone, Mumbai
East Zone, Kolkata
North Zone, Ghaziabad

CDSCO Headquarter
The CDSCO HQ is responsible for:
• Taking appropriate regulatory decision and action regarding
drug safety
• Propagating medicine safety related decisions to
stakeholders
• Provide administrative and Technical support to run PvPI

Regional Centres under PvPI
These regional centres are recognized as Regional Resource Centre
• Eastern Region: IPGMER, Kolkata
• Western Region: KEM Hospital, Mumbai
• Northern Region: PGIMER, Chandigarh
• Southern Region: JSS Hospital, Mysore

What information should be reported ?
ANY INFORMATION
on an ADR or lack of efficacy connected with the use of a medical device/
drug product
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 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

Whom to Report?
Use the ‘Suspected Adverse Drug Reaction Reporting Form’ to report
any ADR
Form available in all AMCs or download from www.ipc.gov.in or
www.cdsco.nic.in
The filled reporting form can be submitted to the AMC or directly to the
NCC
A reporter can also mail the form at pvpi.ipcindia@gmail.com
Toll free number 1800-180-3024 for reporting ADR

Data Flow
Once the Medical institute is enrolled under PvPI, the AMC starts reporting
ICSRs to NCC via a VigiFlow
These ICSRs are then assessed at NCC for quality of data and if found
valid, they are further committed to the global drug monitoring centre
“Uppsala Monitoring Centre” in Sweden
But if the data is not complete or valid, then the ICSRs are reverted back
to their concerned AMC with the query or necessary comments, so that the
respective ICSR can be corrected or completed and sent to NCC again for
evaluation
The data from NCC is also sent to CDSCO, as and when required

Flow of data at regional, national and international level

Assessment of Individual Case Safety
Reports
The quality of the ICSR is assessed for completeness of information and is
reviewed for:
Quality of documentation: e.g. completeness and integrity of data, quality
of diagnosis, follow-up.
Coding: Drug names should be registered in a systematic way, for
example by using the WHO Drug Dictionary (which is based on the ATC
classification). For the coding of the adverse events the WHO Adverse
Reaction Terminology (WHOART) and internationally recognised
terminology (e.g. MedDRA) should be used.
Relevance with regard to the detection of new reactions, drug regulation,
or scientific or educational value

The following questions especially may be asked-
 New drug - a new drug shall continue to be considered as new drug for a period
of four years from the date of its first approval or its inclusion in IP, whichever is
earlier.
 Unknown reaction- Not included in the approved Summary of Product
Characteristics
 Serious reaction- Results into either death, life-threatening condition,
hospitalisation or prolonged hospitalisation, disability, congenital anomaly,
required intervention to prevent permanent impairment/damage or any other
medically important condition
Identification of duplicate reports: Certain characteristics of a case (sex, age or
date of birth, dates of drug exposure, etc.) may be used to identify duplicate
reporting.
Causality assessment: With few exceptions, case reports describe suspected
adverse drug reactions. The likelihood of a causal relationship between drug
exposure and adverse events must be validated

Utilization of the Data
Signal generation and strengthening: A major aim of pharmacovigilance
is the early detection of signals with regard to possible adverse reactions.
A signal may be strengthened by further analysis can help the regulatory
system in performing regulatory activities
Drug regulation: After approval of a medicinal product, all available
domestic and international safety information is continuously monitored by
the drug regulatory authority and MAH. The PvPI data can be useful in
resolving the problems by adaptation of the approved product information
(inclusion of new adverse effects and warnings)
Education: The information from PvPI data is useful in updating the
knowledge of healthcare professionals during continuous medical
education programme on pharmacovigilance

EXPANSION OF PvPI
Medical Council of India (MCI)
Mandatory for every medical college in India to have a Pharmacovigilance
committee, as per regulations of Medical Council of India, 2010
Haemovigilance
COLLABORATION BETWEEN NIB AND PvPI
IPC in collaboration with National Institute of Biologicals (NIB) has launched
Haemovigilance Program of India

EXPANSION OF PvPI
Revised National TB Control Programme (RNTCP)
COLLABORATION BETWEEN RNTCP AND PvPI
In order to improve patient care and safety in relation to the use of anti-
tubercular drugs
RNTCP formally collaborated with PvPI on October 11th, 2013
Participation of Nursing Professionals
NCC-PvPI oraganized a meeting with president Nursing Coumcil of India
(NCI), on July 16, 2014, New Delhi to initiate the participation of nursing
professionals in PvPI.

EXPANSION OF PvPI
National AIDS Control Organization (NACO)
COLLABORATION BETWEEN NACO & PvPI
To ensure the safety of ARV medicines used in the programme, the Indian
Pharmacopoeia Commission and the National AIDS Control Organization
(NACO) formally agreed on 15th September 2014
ADR Monitoring Centres (AMCs)
 All MCI approved teaching hospitals established as AMCs under the PvPI
 Total number of AMCs in India till now is 150
 Department of Pharmacology, MAMC has been established as an AMC
under the PvPI

PV - Role of Healthcare professionals
Spontaneous reporting of adverse reactions is of greatest importance for
obtaining information about adverse drug reactions (ADRs) after granting
the marketing authorization
The most important role and also the greatest responsibility belong to
healthcare professionals. Their active participation is prerequisite for the
existence of an effective national drug safety monitoring
For HCPs, the emphasis should be on education and training, both at the
undergraduate and graduate level, to recognize ADRs and knowing what,
how and where to report them, e.g. by practicing how to fill out a Report
form
ADR Sources at Hospital level can be –
1) Patient Case Sheet
2) Discharge Summary Report

Various ADR forms in spontaneous
reporting
FDA Medwatch 3500 form – USA
Yellow Card – UK
CIOMS Form I – WHO
Each CDSCO form / ADR form contains following critical elements –
a) Patient identifiability
b) Reporter /HCP c) ADR d) Drug information
This ADR data archived in local hospital database/mobile apps interfaced
to CDSCO Vigiflow – Vigibase

Integrated PV & Public Health Program

Conclusion
India is now considered to be a hub for clinical research
The DCGI has shown its commitment to ensure safe use of drugs by establishing
the National Pharmacovigilance Program
More and more clinical trials are now being conducted in India and business
process outsourcing (BPOs) based in India are now also undertaking
pharmacovigilance projects from MNCs
Healthcare professionals, consumer groups, NGOs and hospitals should
appreciate that there is now a system in place to collect and analyze adverse
event data
They should start reporting adverse events actively and participate in the National
Pharmacovigilance Program to help ensure that people in India receive safe
drugs
With the help and proper coordination of all stakeholders, we can definitely build
a world-class pharmacovigilance system in India

References
https://www.who-umc.org/global-pharmacovigilance/who-programme/
https://vaccine-safety-training.org/global-vaccine-safety-datanet.html
International Journal of Clinical Pharmacy https://doi.org/10.1007/s11096-
018-0657-1
Kumar A. Past, present and future of pharmacovigilance in India. Syst Rev
Pharm 2011;2:55-8
http://www.ipc.gov.in/PvPI/pv_home.html
http://z.umn.edu/ INNOVATIONS 2015, Vol. 6, No. 1, Article 189

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