Article

Ensuring Patient Safety - Launching the New

Pharmacovigilance Programme of India
Dr. Y. K. Gupta*, Professor, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi
Co-ordinator, Pharmacovigilance Programme of India

Pharmacovigilance is defined by the World Health Organization (WHO) as "the science and activities relating to the detection,
assessment, understanding and prevention of adverse effects or any other drug related problem". An adverse drug reaction (ADR)
has been defined as any noxious, unintended and undesired effect of a drug which occurs at a dose used in humans for prophylaxis,
diagnosis, therapy or modification of physiological functions (WHO).

Adverse drug events lead to significant mortality and morbidity world over. In developing countries, comprehensive information on
the safety of drugs used in the patient population is meagre and very few studies have been carried out to detect the incidence of
ADRs in the young and the elderly population.

Although, the thalidomide tragedy stressed the need for an effective pharmacovigilance system, it was the withdrawal of rofecoxib
that renewed interest in drug safety mechanisms. Safety issues with other drugs like erythropoetin, rosiglitazone, rimonabant have
also highlighted the need for an effective and comprehensive pharmacovigilance system.

Brief history of The National Pharmacovigilance programme now rechristened as the

Pharmacovigilance in India
Even though pharmacovigilance is still
in its infancy, the concept is not new to India.
It was not until 1986 that a formal adverse
drug reaction (ADR) monitoring system
consisting of 12 regional centers, each
covering a population of 50 million, was
proposed for India. In 1989, under the aegis
of the Drug Controller of India, six regional
centres were set up in Mumbai, New Delhi,
Calcutta, Lucknow, Pondicherry and
Chandigarh. In 1997, India joined the WHO
Programme for International Drug Monitoring
managed by the Uppsala Monitoring Centre,
Sweden. The centre in New Delhi (at
Department of Pharmacology, AIIMS) was
identified as the national centre, while the
centre in Mumbai (at KEM Hospital) was
identified as the WHO special centre. Of the
six centres, only the centres in Mumbai and
New Delhi were active, yet spontaneous
reporting of ADRs was poor. The monitoring
centres were considered ad hoc and
appropriate levels of funding were not made
available, which put severe constraints on
them. Recognising the need for improved
ADR monitoring in India, the Government
of India sent a proposal to the World Bank
for funding. The World Bank approved the
proposal with an annual grant of $US 0.1
million for 5 years and the National
Pharmacovigilance programme was
launched in November 2004.
Program (NPVP) was overseen by the
National Pharmacovigilance Advisory
Committee based in the Central Drugs
Standard Control Organization (CDSCO),
New Delhi. 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), collated information from
all over the country and sent it to the
Committee as well as to the Uppsala
Monitoring centre in Sweden. Three regional
centers reported to the Mumbai center and
two to the New Delhi. Each regional center
in turn would have several peripheral centers
reporting to it. The program had three broad
objectives: the short-term objective was to
foster a reporting culture, the intermediate
objective was to involve a large number of
healthcare professionals in the systems in
information dissemination and the long-term
objective was for the program to be a
benchmark for global drug monitoring.
However, the World Bank funding for the
national programme ended in mid 2009 and
the programme was temporarily suspended.
Recognizing the need to restart the
national pharmacovigilance programme, in
a brainstorming workshop jointly organized
by Department of Pharmacology, AIIMS and
CDSCO in late 2009, the framework of the
new programme was formulated. The
Pharmacovigilance programme for India
(PvPI) is operational from mid July 2010.
Role of Pharmacovigilance
programme in drug safety
monitoring
Safety problems with pharmaceutical
products can be identified in Phase I, Phase
II, and Phase III clinical studies conducted
prior to regulatory approval of the drug.
However, the numbers of patients enrolled
in these studies are usually inadequate to
allow for reliable detection of less frequent
adverse events. The routine three phase
clinical trials do not always guarantee safety
of a new drug as the human trials usually
cover only a few thousands of volunteers, but
several lakhs of people take the drug after it
is allowed to be marketed. It is essential to
follow a drug from pre-marketing clinical
studies into the real life conditions. As a new
drug is released, safety issues can arise due
to several reasons like trial participants not
being a true representative of end users,
genetic variations in the patient population,
co-morbidities and concomitant medications
and little prior information on the use of drug
in special populations like elderly, children
and pregnant women. One option for
improving the government's ability to detect
adverse events before a regulatory approval
is to increase the numbers of patients
enrolled in pre-registration clinical trials,

*E-mail : yk.ykgupta@gmail.com

Pharma Times - Vol 42 - No. 08 - August 2010 21

 particularly in the larger Phase III trials. After
new drug products have received approval
for marketing, the Drug regulatory authorities
rely largely on a voluntary spontaneous
reporting system to generate signals of a
safety problem.
The need for pharmacovigilance is well
understood by the government and the
scientific community in the country, in the
context of increasing number of recalls of
drugs worldwide from the market due to their
serious side effects. Recent withdrawal of
certain blockbuster drugs in the US and
Europe is a testimony to the successful
functioning of ADR reporting system in
developed countries.
All medicines (pharmaceuticals and
vaccines) have side effects. Some of these
side effects are known, while many are still
unknown even though that medicine has
been in clinical use for several years. It is
important to monitor both the known and
hitherto unknown side effects of medicines
in order to determine any new information
available in relation to their safety profile. In
a vast country like India, with a population of
over 1.2 billion which has vast ethnic
variability, different disease prevalence
patterns, practice of different systems of
medicines, different socioeconomic status
it is important to have a standardized and
robust Pharmacovigilance and drug safety
monitoring programme for the nation.
Collecting this information in a systematic
manner and analyzing the data to reach a
meaningful conclusion on the continued use
of these medicines is the rationale to institute
this program for India.
Since, there are considerable social
and economic consequences of ADRs
there is a need to engage health-care
professionals, in a well structured
programme to build synergies for
monitoring ADRs. The purpose of the
Pharma-covigilance Program of India is to
collect, collate and analyze data to arrive
at an inference to recommend regulatory
interventions, besides communicating
risks to healthcare professionals and the
public.
SWOT analysis of
Pharmacovigilance in India
The Pharmaceutical industry in India is
valued at Rs. 90,000 Crore and is growing
at the rate of 12 - 14 % per annum. Exports
are growing at 25 % Compound Annual
Growth Rate (CAGR) every year. The total
exports of Pharma products are to the extent
of Rs. 40,000 Crore. India is now being
recognized as the 'Global pharmacy of
Generic Drugs' & has distinction of providing
generic quality drugs at affordable cost. India
22 Pharma Times - Vol 42 - No. 08 - August 2010
is also emerging rapidly as a hub of Global
Clinical trials & a destination for Drug
Discovery & Development.
Further, more & more new drugs are
being introduced into the country which
include New Chemical Entities (NCE), high
tech pharma products, vaccines as well as
new dosage forms, new routes of drug
administrations and new therapeutic claims
of existing drugs.
Such rapid induction of NCEs and High
tech Pharma products in the market throw
up the challenges of monitoring Adverse
Drug Reactions (ADRs) over large
population base.
(a) Strengths
The biggest strength of India is its large
population and a large pharmaceutical and
biotech industry base. According to the
report of the National Commission on
population in the year 2000, India was
projected to have 1 billion people, i.e. 16
percent of the world's population
If current trends continue, India may
overtake China in 2045, to become the most
populous country in the world. While global
population has increased threefold during
this century, from 2 billion to 6 billion, the
population of India has increased nearly five
times from 238 million (23 crores) to 1 billion
in the same period.
According to the OPPI and Ernst and
Young report published in 2009, It has
manufacturing prowess in both APIs, India
is the 3rd largest player in the world with
500 different APIs and in formulations where
it manufactures 60,000 packs across 60
therapy areas. India currently accounts for
8% of the global pharmaceutical production
making it the world's 4th largest
pharmaceutical producer.
Also, the focus is on to further enhance
India's capability to contribute more
medicines to the world by increasing the
focus on research and development. The
Indian government has recognized the need
to build an environment conducive for
research and innovation and has planned/
implemented a number of initiatives to
provide the much needed impetus to
research and innovation in pharma & biotech.
The Government of India is embarking on a
major multi-billion dollar initiative with 50%
public funding through a public private
partnership model to harness India's
innovation capability. The vision is to catapult
India into one of the top five pharma
Innovation hubs by 2020 with one out of
every five to ten drugs discovered worldwide
by 2020 coming from India. With a large
population being exposed to a large portfolio
of drugs there is a huge mine of data that
can be explored to learn more about the
safety profile of our drugs.
(b) Weaknesses
As per the estimates during 2009-10,
the allocation of budget for health by the
Centre stood at Rs 21680 crore, which
accounted for 2.1 per cent of the total
expenditure and 0.35 per cent of the GDP
of India. The overall spend for the vital
healthcare sector always remained far less
than half a percent of the India's GDP
hovering around a maximum of 2% of the
total budget.
In comparison The United States spent
16% of its national income (GDP) on health
in 2007. France, Switzerland and Germany,
the countries which, apart from the United
States, spend the greatest proportion of
national income on health, spent over 5
percentage points of GDP less: respectively
11.0%, 10.8% and 10.4% of their GDP.
Thus low availability of spend on health
has an impact on the manpower and
resources that are available for
implementing programs and issues of
national importance such as
pharmacovigilance. A case in point is the
erstwhile National Pharmacovigilance
program launched in 2004. One of the
reasons for the failure of the program was
the continuous availability of funds to sustain
the program.
(c) Opportunities
The opportunities are immense. India
constitutes 16% of the world's population
and is one of the largest source of human
biodiversity, consisting of 4635 culturally and
anthropologically well-defined populations
with little or no gene flow between them.
Hence, study on Indian populations,
who are known for their cultural and genetic
diversity, not only provides insight into their
complex origin, history and relatedness, but
also helps in understanding molecular
pathology of genetic diseases. As each
Indian population is unique in their genetic
composition, etiologies of genetic diseases
are often different from other global
populations. Indian populations are unique
in their genetic origin as well as in the
mutations underlying in the susceptibility to
disease. Therefore, what is true for other
global populations, in terms of their genetic
basis for disease susceptibility, may not be
true for Indian populations.
Collection of vital data on the behavior
of drugs in the Indian population will reveal
additional information on the safety profile
of these drugs. Once the ADR data is
collected, signaling can help determine if a
particular ADR was caused by a particular
drug and if it had any correlation with the
genetic diversity of the Indian population.
Moreover, with more 300 medical
colleges, 230 dental colleges, 830 pharmacy
colleges and 657 recognized nursing
colleges, there is a great opportunity for India
to tap the potential human resources
required for an effective pharmacovigilance
system.
(d) Threats
Ensure availability of and management of
funds:
Advance contingency fund and salary
of the technical associates appointed at the
ADR monitoring centre should reach to the
centre coordinator a month in advance i.e.
in the month of December for first half and
May for second half of the year. Centre
coordinator should send the utilization
certificate along with original bills duly
verified to the CDSCO zonal office within 15
days of the following month.
Conduct frequent training and awareness of
Pharmacovigilance:
AMC coordinator must organize at least
two meetings with HCP in their areas.
Expenses should be met from the
contingency fund. Coordinator should be the
resource person for such meetings.
Detect and respond to under reporting of
ADRs:
Periodic sensitization of HCP through
various modes viz poster, pamphlets, SMS,
etc. by the center coordinator will improve
AE reporting. The technical associate
appointed at the centre should visit daily to
wards, OPDs and private clinics etc.
Undertake appropriate measures to create
awareness among the public through mass
media to increase the reporting.
Ensure quality of filled ADR forms:
Quality Review Panel (QRP) will ensure
quality of reports during their visit to the AMC
and also at the PvPI National Coordinating
Centre (NCC).
Proper supervision of functioning of the
centers:
A Quality Review Panel (QRP) shall
visit a sample set of AMCs at least once a
year to monitor functioning of these centres.
If functioning of the Centre is found
unsatisfactory or not working as per SOPs,
an appropriate warning shall be issued. The
report should decide the status of the centre.
If performing well, the AMC shall be given
due recognition for its achievements.
Feed back to the Health Care Professionals
AMC coordinator will circulate the
reports generated by the PvPI National
Coordinating Centre and give feedback of
the programme progress to the Health Care
Professionals.
Attitude towards ADR
reporting and practices of
health care professionals
towards ADR reporting
Adverse events are preventable if the
clinician maintains a high degree of
suspicion and pays close attention to details
regarding adverse events following drug
administration. Another way of prevention is
by efficient reporting and monitoring of ADRs
which can help in generation of safety
signals. However, under-reporting of ADRs
by health care physicians is a major
problem, even in countries like, UK, US and
Japan, where pharmacovigilance systems
have been well established.
Numerous studies have attempted to
understand the attitude of physicians
towards reporting ADRs. European studies
have revealed that physicians inclined to
report only adverse reactions that are
serious, unusual or rare and are do not report
non-serious or common adverse reactions.
Unlike that in the west, few such studies
have been carried out in India. Surprisingly,
these studies have revealed that many
physicians are unaware of the pharma-
covigilance programme and the ADR
reporting systems existing in the country.
Other reasons for low ADR reporting rates
are lack of feedback regarding the reports
and lack of time due to high clinical load.
Nevertheless, many of these factors are
potentially modifiable.
The studies have also attempted to
identify, possible measures that may
enhance involvement of physicians in the
ADR reporting system. These measures
include, creating awareness about
pharmacovigilance, implementing ADR
reporting as integral part of UG, internship
and PG training, providing active manpower
to collect ADR reports from busy clinicians,
provision of feedback to reporting health care
professionals, automatic membership to
"ADR reporters club", provision of
information about drug safety and
medication errors, involvement of nurses
and paramedical staff in reporting ADRs and
giving small economic incentives to regular
reporters. In addition, impressing upon the
clinicians the importance of reporting
relatively common ADRs, in order to identify
drug epidemics, may also help in increasing
the volume of ADR reports.
However, although many of these
measures have been suggested to increase
Pharma Times - Vol 42 - No. 08 - August 2010
the reporting rates, only few, such as
awareness and training programmes,
provision of feedback to reporters, involving
nurses and giving small economic incentives
for reporting have actually been tested and
proven to increase the reporting rates.
Stakeholders in
Pharmacovigilance
Patients
The patients are the most important
stakeholders in drug safety monitoring
system as they are the ones who experience
the adverse drug reactions. Prompt
identification and feedback to the prescribing
physician regarding ADR following usage of
a drug is imperative to capture the harmful
effects of the drug early in the product cycle.
Moreover, it is also important for patients to
maintain a high index of suspicion for
counterfeit drugs especially when a drug that
is usually effective fails to provide the same
level of effectiveness. Generally, in the more
developed countries, patients can directly
report ADRs to the pharmacovigilance
centres. However, in India due low literacy
and lack of understanding of medical signs
and systems, patients notifiy the physician
who after proper history taking report the
ADR to the pharmacovigilance centres.
Pharmaceutical Industry
The amended schedule Y (2005) of the
Drugs and Cosmetics Act mandated the
submission of periodic safety update reports
(PSURs) for a period of four years
postmarketing. Moreover, it was recognized
that there was a need to carry out safety
surveillance studies to answer specific drug
related issues. In addition, as many drugs
are also licensed in other countries, safety
data from those regions was required to be
collected, analyzed and reported in PSURs.
This change has led to massive expansion
of pharmacovigilance activities in the
industry. However, the nature of such
activities remains focused to only those
drugs manufactured by it. Unfortunately,
even after amendments in the regulations,
the quantity and quality of ADR data provided
by the industry is often below specified
standards. Further, as industry driven
pharmacovigilance is mandated only for new
drugs, ADRs related to generics may be
missed. This may be due to lack of staff
experienced in pharmacovigilance.
Nevertheless, as awareness about drug
safety monitoring is increasing, the industry
has the responsibility of training its
professional sales representatives and
pharmacovigilance executives to interact
with treating physicians and collect ADR
reports.
23
 Regulators
The drug regulator is one of the most
important stakeholders in the Pharma-
covigilance system. The onus of constantly
reviewing updated drug safety information
and ensuring that public at large is protected
from the possible adverse effects of drugs
constantly lies with the drug licensing
authority. Moreover, regulators are often
faced with the prospect of either banning,
suspending the marketing, or changing the
safety specifications in the label of drugs with
potential safety issues reported from other
regions of the world. Therefore
pharmacovigilance data becomes a major
decision making tool in the hands of the
regulator. In addition, constant generation
and review of safety data of drugs also
bolsters public confidence in the licensing
authority.
Academicians - Post graduate and
undergraduate training and curriculum
One of the key skills that undergraduate
medical students should develop during their
undergraduate training is to be prepared for
safe medical practice. This concept is
usually diluted or ignored in most medical
curricula and course designers usually focus
on content such as causes of diseases,
pathogenesis, clinical picture, investigations,
differential diagnosis and case management.
The focus should also be on risk assessment
of medications, evaluation of adverse
effects, contraindications and drug
interactions while designing the course for
pharmacology and medicine curricula. The
undergraduate students should especially be
taught about common medication errors that
occur with high risk drugs such as warfarin,
hypoglycaemic agents, opioids and
corticosteroids and measures to prevent
them. The students can also play active role
in collecting ADR reports during their clinical
wards posting.
Interns and PG students can play a
major role in interacting with patients and
their peers in the clinical departments. Their
training should be oriented towards,
identifying ADRs, assessing their
preventability and reporting them. Besides
they can, by interacting with their peers and
other para medical staff, increase the
awareness about pharmacovigilance
systems and enhance ADR reporting rates.
Moreover, interns and PG students are an
invaluable source for collecting, analyzing
for causality and reporting ADRs and
authoring case reports and case series and
cohort event monitoring studies. However,
their training should be largely self directed
and dynamic, albeit with proper mentoring,
thus enabling them to provide appropriate
and up-to-date feedback regarding ADRs
and other drug related problems to others.
24 Pharma Times - Vol 42 - No. 08 - August 2010
Role of other partners
Role of other stakeholders like media
representatives, lawyers, health insurance
providers and non-governmental
organizations in development of robust
pharmacovigilance system and sound drug
policies cannot be undermined. Media by
promoting good ADR reporting practices and
their relevance to the patients and consumer
groups can play an important role in
encouraging them to report the adverse
events to their clinicians. These groups by
voicing public opinion and expectations can
facilitate the evolution of a pharma-
covigilance programme that enjoys favorable
public opinion and trust. Co-operation and
communication with these partners needs
to be as clear and open as possible.
Misrepresentation of facts in the form of
'attention grabbing' drug safety concerns can
wreak havoc on the public confidence in the
existing drug safety policies as well as the
pharmaceutical industry.
Synergy between academia, regulator
and industry for effective
pharmacovigilance
Pharmacovigilance cannot be an
exercise in isolation. In order to be
meaningful, it has to involve all the major
stakeholders. A collaborative model involving
the three major stakeholders; the academia,
the industry and the regulators has been
envisaged to enhance the effectiveness of
the pharmacovigilance system in India.
Under the erstwhile pharmacovigilance
programme, drug safety monitoring activities
was more or less restricted to a few centres
and were carried out by highly motivated
people (mostly pharmacologists) despite
financial / resource constraints. Moreover,
these activities were secondary to their
primary job of teaching. Owing to manpower
and resource constraints (lack of dedicated
computers, access to literature sources,
poor archiving facilities etc.) the quantity and
the quality of ADR data collected was
insufficient to propel any real regulatory
decision regarding drug safety. Further, as
the onus was on "all drugs and all ADRs",
and there was a definite loss in focus.
However, the new pharmacovigilance
programme envisages involving most of the
approximately 300 registered medical
colleges across the country to ensure that
meaningful and country specific data
regarding ADRs can be collected from all
parts of the country. Not only spontaneous
report collection, the new programme will
also encourage and facilitate monitoring
centres to undertake and report
postmarketing safety studies, drug use
reviews and registry/database based studies
independently or in collaboration with
industry partners.
After submission of PSURs were made
mandatory in India as per the amended
schedule Y of the Drugs and Cosmetics Act,
pharmacovigilance as a core activity within
the pharmaceutical industry increased
tremendously. However, within a company,
the nature of such activities remains focused
to only those drugs manufactured by it.
Therefore to broaden the scope of drug
safety monitoring, it is proposed that industry
synergizes and supports the initiative of
academia in undertaking pharmacovigilance
projects, especially cohort event monitoring,
safety trials and other pharma-
coepidemiological studies. Further, industry
inputs and support for organizing training
workshops, symposia etc, in collaboration
with the academia and regulators will also
help in increasing the awareness and
outreach of the programme amongst the
prescribers and will make it more effective.
Data generated from the collected ADR
reports enable the regulators to make
important regulatory decisions such as
banning, restricting the use or making
changes in the label of a drug. However, in
India due to the absence of any substantial
ADR data, regulators are often forced to rely
on western ADR data to make such
decisions. Under the new pharmacovigilance
programme, a proactive role for regulators
has been envisaged, wherein they do not
merely end-users of ADR data but also
facilitate and oversee academia-industry
collaborative pharmacovigilance projects.
The new programme also seeks to actively
involve the regulators in drug safety training
programmes, providing operational support
to the ADR monitoring centres, carrying out
periodic quality assurance activities and
assuring continued funding for sustaining the
programme.
Pharmacovigilance
Programme for India (PvPI)
The Central Drugs Standard Control
Organization (CDSCO) under the aegis of
Ministry of Health & Family Welfare,
Government of India in collaboration with
Department of Pharmacology, All India
Institute of Medical Sciences (AIIMS), New
Delhi has initiatited a nation-wide
pharmacovigilance programme for
protecting the health of the patients by
assuring drug safety which will include data
for drugs, biologicals, vaccines, diagnostics
and medical devices from public and private
sector. The comprehensive national
programme is coordinated by the
Department of Pharmacology at AIIMS as a
National Coordinating Centre. The centre
operates under the supervision of a Steering
Committee.
 The Goal of the program is to ensure
that the benefits of medicine used outweigh
the risks and thus safeguard the health of
the Indian population. The objectives are:
z To monitor Adverse Drug Reactions
(ADRs) in Indian population
z To create awareness amongst health
care professionals about the
importance of ADR reporting in India
z To monitor benefit-risk profile of
medicines
z Communicate findings with all key
stakeholders
z Generate independent, evidence based
recommendations on the safety of
medicines
z Support the CDSCO for formulating
safety related regulatory decisions for
medicines
z Create a national centre of excellence
at par with global drug safety monitoring
standards
Key features of this programme
1. There is an organized project
management approach to the
programme.
2. All the key stakeholders have been
involved in this namely (and not limited
to) Government, Academia, Health
Care professional bodies, Industry,
National Immunization programmes,
WHO-Uppsala monitoring centre,
Industry professional bodies, Medical
colleges, autonomous institutes,
corporate hospitals, CDSCO Zonal
centres.
3. Data on Indian population will enable
informed decision making by the Indian
regulatory authority by performing
signal detection once the data reaches
a threshold size
4. The CDSCO Zonal centres will provide
administrative oversight to the ADR
monitoring centres at the medical
colleges.
5. Training and Quality assurance are key
essential elements intertwined with
every aspect of the programme.
Framework of the new programme
The programme is envisaged to be
rolled out in three phases. Phase I would
include 40 adverse drug reaction monitoring
centres (AMC) and will be rolled out in 2010.
The programme would be expanded in
Phase II to include up to 140 MCI recognized
medical colleges by 2011. Phase III would
ultimately cover the healthcare system by
2013. Phase I will be further divided into
phase Ia and Ib. Phase Ia will involve
upgrading 10 centres in terms of
infrastructure (computer and ancillaries).
Phase Ib will include the rest of the 40
centres by end of 2010. The centres for
Phase Ia have been shortlisted based on
letter of intent received from interested
faculty, duly forwarded by the head of the
institution. The AMCs will get operational and
logistic support from their respective zonal
CDSCO centres, situated at Ghaziabad,
Kolkata, Mumbai and Chennai. The zonal
CDSCO centres will be under administrative
control of the CDSCO headquarter at New
Delhi.
The coordinating centre of
Pharmacovigilance Programme for India will
be housed at Department of Pharmacology,
All India Institute of Medical Sciences, New
Delhi and will provide technical support to
the CDSCO headquarter. All the centres
under the programme will function in
accordance with the protocol and SOPs
developed by expert committees.
Fig. 1. Proposed growth phases of
Pharmacovigilance Programme for India
ADR data flow
Adverse drug reaction reports will be
collected at the ADR monitoring centres
(AMCs). The pharmacovigilance staff at the
AMCs will check for validity of the report and
if possible conduct provisional causality
assessment. The ADR forms will then be
dispatched to the co-ordinating centre as per
the SOPs. The AMC staff will also maintain
a log of all the centre activities. Selected
AMCs will also carry out focused ADR
monitoring of drugs in the focused ADR
monitoring watch list. The co-ordinating
centre will conduct causality assessment
and upload the reports into the national
pharmacovigilance database. The co-
ordinating centre will prepare a consolidated
report of ADRs collected at defined time
intervals. All the ADRs from all other sources
(industry, Health care professionals, national
immunization programmes etc.) will also be
databased at the co-ordinating centre.
The centre will also implement and
integrate pharmacovigilance activities into
public health programmes involving mass
usage of drugs, such as for anti-malarial,
anti-tubercular and anti-retroviral drugs.
Lastly, the integrated ADR data will be
Pharma Times - Vol 42 - No. 08 - August 2010
transmitted through vigiflow interface into the
UMC ADR database where signal processing
can be carried out.
Collaboration with World
Health Organization and
the Uppsala Monitoring
Centre (UMC)/WHO
WHO and UMC work with and/or
provide technical support to more than 94
countries worldwide. The long term objective
of the PvPI is to establish a 'Centre of
Excellence' for Pharmacovigilance in India.
To achieve this objective, the PvPI National
Coordinating Centre will collaborate with the
WHO Collaborating Centre - Uppsala
Monitoring Centre (UMC) based in Sweden.
z Training of the staff at the PvPI national
coordinating centre at AIIMS, the ADR
Monitoring centres in medical colleges
across the country
z Usage of UMC's Vigiflow software (for
medicines) and Paniflow (for vaccines)
z Access to Vigibase, which contains
worldwide medicines safety data
z Access to early information about
potential safety hazards of medicines
(worldwide data)
z Technical collaboration for Pharma-
covigilance Programme of India
z Technical collaboration for a regular
publication that will be issued by the
PvPI National Coordinating Centre for
distribution to the ADR Monitoring
centres and other health care
professionals.
Linking Pharmacovigilance
with Public Health
Programmes
Drug safety concerns one and all and
hence a robust pharmacovigilance system
is the clear need of the present and future
times. A good plan is half the job done.
However successful start is just the
25
 beginning and it is important to stay focused.
A continued interest of all the stake holders
in pharmacovigilance activities will
determine the success of the programme.
One of the many ways to ensure ongoing
interest in pharmacovigilance is to include it
in the public health programme. This will
serve the dual purpose of continued interest
in drug safety at the grass root level of health
care system as well as catering to the safety
issues important for public in general.
One such issue important for India is
the recent switch over to artemisinin
combination therapies for treatment of
malaria in view of increasing chloroquine
resistance. In this respect, the National
Institute of Malaria Research, in
collaboration with the National Coordinating
Centre at Department of Pharmacology,
AIIMS initiated a World Bank funded study
for pharmacovigilance of anti-malarial
medicines. This is the first attempt to involve
pharmacovigilance in a public health
programme in India. The study aims to
assess the safety of artemisinin combination
therapies in real life settings in India. The
ultimate goal is to influence the behavior of
the healthcare physicians in the remote
areas of the country with respect to adverse
event reporting.
Following successful implementation of
pharmacovigilance in malaria, the next step
should be involvement of other public health
programmes like HIV, Leprosy, Tuberculosis
etc. Such efforts will help in making the
pharmacovigilance programme a self-
sustaining system if the logistics can be
taken care of. It will also help in building
patient trust in the healthcare system which
is the eventual expectation from the
Pharmacovigilance programme in India.
Linking
pharmacogenomics with
pharmacovigilance
Many different types of drugs are
available to treat a wide variety of disorders.
Why some patients respond to a particular
drug and others do not respond, or why
some patients tolerate a drug well and others
are intolerant of the same drug, are important
clinical issues in medicine. Genetic
differences among patients may contribute
to differences in medication response, as
well as the development of adverse effects.
'Pharmacogenomics' and 'pharma-
cogenetics' refer to the use of molecular
genetic approaches to understand
differences in drug response and tolerability.
Many types of putative ADRs are likely to be
complex and to have multifactorial etiologies.
Examples include the metabolic syndrome,
tardive dyskinesia, suicidality, hepatic
dysfunction and cardiac abnormalities
26 Pharma Times - Vol 42 - No. 08 - August 2010
following drug administration. These
conditions are clinically significant and often
linked to drug therapies, but they cannot be
easily or solely attributed to a drug exposure.
Pharmacogenetics can help identify
individuals who are susceptible to adverse
drug reactions (ADRs) has the potential to
reduce the personal and population costs of
drug-related morbidity.
The most common enzyme deficiency
worldwide is glucose-6-phosphate
dehydrogenase (G6PD) deficiency, with
many allelic variants. It is associated with
acute haemolysis on exposure to oxidising
drugs such as primaquine, chlorproguanil-
dapsone, sulfonamides, and sulfones,
nitrofurantoin, nalidixic acid, quinine,
flutamide Phenotypic tests for G6PD
deficiency are recommended before using
drugs such as primaquine, but it is not known
how often this is carried out. Abacavir an HIV-
1 reverse transcriptase inhibitor, causes a
hypersensitivity reaction (skin rash, fever,
gastrointestinal and respiratory effects) in
about 5% of patients and is associated with
an HLA allele, HLA-B*5701. Pre-prescription
genotyping prevents abacavir hyper-
sensitivity and is cost-effective. In Europe,
screening for HLA-B*5701 is now mandatory
before prescribing abacavir. Similarly, severe
immune-mediated adverse effects including
Stevens-Johnson syndrome and toxic
epidermal necrolysis has been reported with
carbamazepine. In Han Chinese patients this
is associated with HLA-B*1502, and the drug
is avoided in those with this phenotype. In a
recent study, the investigators evaluated the
implications of single nucleotide
polymorphism of CYP2C9 and CYP2C19
genes on phenytoin pharmacokinetics in
healthy South Indian voulnteers and
concluded that *2 - *3 alleles of CYP2C9
led to decreased hydroxylation of the drug,
thereby increasing the risk of ADRs
Although promising, the eventual
impact of pharmacogenomic profiling for
identification of ADR susceptibility among
individuals would depend upon incidence of
drug related toxicity, prevalence of variant
alleles, severity of consequences and also
the availability of rapid, reliable and cost
effective assays. Several researchers have
proposed the integration of genomic
information with the pharmacovigilance
databases, which can not only enhance
signal detection but also aid in determining
whether genotyping should be performed
prior to initiation of drug therapy. However,
several key operational, regulatory, ethical
and legal issues need to be addressed
before the potential role of pharma-
cogenomics in ADR detection and
prevention can be realized. These include
the complexity of database which integrates
information on drug transporters,
metabolism and therapeutic targets, public
private sector cooperation, funding of
research, ensuring privacy and
confidentiality of data to prevent
stigmatization as well as educating the
medical and lay communities.
India's 2020 Vision for
Pharmacovigilance
1. Being the second most populous
country in the world, it should constitute
the largest contributor to the adverse
event database as a result of a large
number of ADRs being reported to the
national drugs regulatory authority.
2. The actual number of ADRs should
actually show a declining trend as the
country should aim to achieve the real
aim of pharmacovigilance i.e. to provide
safer medicines for the population of
India. The aim therefore should be to
collect data and learn from that data
so much that we are able to take a
decision on continuing or discontinuing
the use of a drug based on its ongoing
risk benefit assessment. The focus
should move from pharmacodiligence
to pharmacovigilance. The target
should be to prevent ADRs and the
associated loss of costs in managing
those ADRs.
3. Each stakeholder to not only be
conscientious of their rights but also
their responsibilities towards the
patients and the society at large
4. The Program for Pharmacovigilance in
India should be viewed as a centre of
excellence and the model pursued and
demonstrated in the past 10 years
should become a role model for the rest
of the world to follow.
5. India should aim to be self dependent
and have its own National Drug Safety
database with electronic reporting
capabilities to all the other major Global
regulatory agencies
6. Globally regulatory agencies in the
world should view India as the Global
Pharmacy of the world and as a
resource of knowledge and a treasury
of information related to the safety of
molecules.
7. Not only will the safety database cover
pharmaceutical products, but also
biological, devices, vaccines and stem
cell therapies.
Acknowledgements
l gratefully acknowledge the
contributions of Dr. Vivek Ahuja, Mr. Paul
Lalvani, Dr. Biswa Mohan Padhy, Dr. Pooja
Gupta and Dr. Ashish Kakkar in preparation
of the article.