Pharmacovigilance: An Overview
Saurabh Nimesh and Vrish Dhwaj Ashwlayan*
Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, NH-58 Baghpat Crossing
Bypass Road, Meerut-250005 Uttar Pradesh, India.
Vrish Dhwaj Ashwlayan, Department. of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, NH-58
Baghpat Crossing Bypass Road, Meerut-250005 Uttar Pradesh, India, Tel: 91-9412493228; E-mail:
Received: May 16, 2018; Accepted: May 30, 2018; Published: May 31, 2018
Citation: Ashwlayan VD, Nimesh S (2018) Pharmacovigilance: An Overview. Int J Pharmacovigil 3(1):1-6.
Pharmacovigilance (PV) plays a key role in the healthcare
system through assessment, monitoring & discovery of interactions
amongst drugs and their effects in human being. Pharmaceutical
and biotechnological products are designed to diagnose, prevent or
cure diseases. India is the world’s second most populated country
with over 1 billion potential drug consumers. Although, India is
participating in the Uppsala Monitoring Center (UMC) programme,
its contribution to that database is relatively small. Signal assessment
is mainly performed to analyse the cause and effect by using World
Health Organization (WHO) scale & Naranjo scale of probability. Signal
detection and its assessment is very vital and complex process. This
article gives a systematic review of the PV in India from its origin to
the current scenario and also discusses the various strategies and
proposals to build, maintain and implement a robust PV system and to
improve the process of ADR reporting in the country.
Keywords: Adverse drug reactions; pharmacovigilance;
spontaneous reporting system; Uppsala monitoring centre; causality
PV was officially introduced in December 1961 with the
publication of a letter in The Lancet by Dr. William McBride, the
Australian obstetrician who first suspected a causal link between
serious fatal deformities (phocomelia), thalidomide used during
pregnancy: Thalidomide was used as an anti-emetic and sedative
agent in pregnant women. In 1968, the 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’. WHO defines PV as ‘the pharmacological
science relating to the detection, assessment, understanding
and prevention of ADRs, particularly long-term and short-term
ADRs of medicines. PV serves various roles such as identification,
quantification and documentation of drug-related problems
which are responsible for drug-related injuries. PV is mainly
the post marketing surveillance (phase-4 study) of drug
development; the main objective of PV is to quantify previously
recognized ADRs, to identify unrecognized ADRs, to evaluate
the effectiveness of medicines in real-world situations, and to
decrease mortality and morbidity associated with ADRs. The
UMC located at Uppsala, Sweden co-ordinates the International
Drug Monitoring program (IDM). Till now there are 104 official
member countries and 33 associate members throughout the
world, including developed, developing and under-developed
countries. India is the world’s second most populated country
with over one billion potential drug consumers. Although, India
is participating in the UMC program, its contribution to this
database is relatively small. This problem is essentially due
to the absence of robust ADRs monitoring system and also the
lack of awareness of reporting concepts among Indian health
care professionals. It is very important to focus the attention of
the medical community on the importance of ADRs to ensure
maximum benefits for public health and safety. In India ADRs are
considered among the leading cause of morbidity and mortality.
Approximately 8% of hospital admissions are estimated due to
ADRs and regarding 8-19% of hospitalized patients experience a
serious ADR. When the FDA approves a new drug or marketing,
its complete adverse events profile may not be known because
of the limitation of pre-approval clinical trials. Typically, clinical
trials for new drugs are not of short durations and are conducted
in populations that number up to 5000, therefore, the most
common dose related ADRs are usually detected in the premarketing
phase while ADRs which are rare and those detected
on long term use are not Figure.No.1 [1-8].
Types of ADR
ADR is a response to a drug which is noxious and unintended,
and which occurs at doses normally used in human being for
the prophylaxis, diagnosis or therapy of disease, or for the
modification of physiological function Table.No.1 .
Historical background of PV
The safety of drug was not the early concern in the history
of drug. The thalidomide tragedy of 1960s opened the eyes of
drug regulators as well as other concern healthcare professionals
to establish a way to ensure drug safety. The mile stone in the
drug safety was the publication of chloroform related death
on The Lancet journal for the first time in 1893. Safety of drug
became the global concern and different initiatives were taken by
Figure 1: Diagrammatic representation of PV
different countries to safeguard the public health safety. The US
FDA act was passed in 1906 for the first time, but it was amended
to control misbranding of ingredients and false advertising claims
after 107 deaths by the use of di-ethylene glycol as a solvent for
sulphanilamide elixir. There were radical changes in the drug
safety issues after the worldwide thalidomide tragedy which was
first reported by an Australian obstetrician, Dr. William McBride
in December 1961.
He reported thalidomide associated serious fatal deformities
(phocomelia) used in pregnancy. This drug had not been
adequately screened for teratogenicity, but similar malformations
were subsequently shown in the rabbit and at high dose in the
rat. In West Germany 4000 individuals were affected. The tragedy
made the world to be more concern about the drug safety,
as efficacy was only the parameter to see the effect of drugs.
Immediately after the tragedy the US FDA act was amended to
compulsory pre-marketing submission of both efficacy and
safety data in 1962. The UK Medicines act was enforced in
1968, however, safety monitoring via ‘yellow card system’ was
introduced in 1964. The drug safety issues were globalised,
strengthened and systematized after the establishment of WHO
Programme for IDM in 1968 [10,11].
Purpose of PV
PV is the science and activities related to the detection,
assessment, understanding and prevention of ADRs or any other
possible drug-related problems. Recently, its concerns have been
widened to include:
1. Herbals Traditional and complementary medicines
2. Blood products
3. Biological products
4. Medical devices
Many other issues are also of relevance to the science
1. Sub-standard medicines
2. Medication errors
3. Lack of efficacy reports
4. Use of medicines for indications that are not approved and for
which there is inadequate scientific basis
5. Case reports of acute and chronic poisoning
6. Assessment of drug-related mortality
7. Abuse and misuse of medicines
8. Adverse interactions of medicines with chemicals, other
medicines, and food
The specific aims of PV are to
1. Improve patient care and safety in relation to the use of
medicines and all medical and paramedical interventions
2. Improve public health and safety in relation to the use of
3. Contribute to the assessment of benefit, harm, effectiveness
and risk of medicines encouraging their safe, rational and
more effective (including cost-effective) use, and
4. Promote understanding, education and clinical training in PV
and its effective communication to the public.
PV has developed and will continue to develop in response
to the special needs and according to the particular strengths
of members of the WHO Programme and beyond. Such active
influence needs to be encouraged and fostered; it is a source
of vigour and originality that has contributed too much to
international practice and standards .
Vigi-Flow is a web-based Individual Case Safety Report (ICSR)
management system that is specially designed for use by national
centres in the WHO Programme for IDM. It can also be used by
pharmaceutical companies or clinical research organisations for
monitoring of their ICSR. Vigi-Flow is based on and compliant
with the ICH E2B standard and is a trademark of the UMC and
maintained by the UMC in Uppsala, Sweden. VIGIBASE is the name
of the WHO global ICSR database measure (IC value) stratified in
different ways and is useful for filter capabilities. It has been in
use for more than 30 years, it is located in Uppsala since 1978
and designed for spontaneous reports, maintained by the UMC.
Yellow Card Scheme
Yellow card schemes (YCS) were applied to spontaneous
reporting systems. The system has become one of the major
international PV resources. The yellow cards are classified into
seven priorities by a member of the scientific staff according to
the drugs and the nature of the ADRs. The YCS is run jointly by
the Medicines Control Agency which is the regulatory agency
and the Committee on Safety of Medicines which is the experts
committee. Since 1991, the YCS has been enhanced by a new
computer system, the ADROIT (Adverse Drug Reaction Online
Information Tracking) system. ADROIT is different from other
databases. Not only does it store the details of the report, but also
the image of the yellow card in the optical system. Multiple users
can view any yellow card on screen at the same time. The reports
are made on priority so that serious ADRs receive early attention
Naranjo’s Probability Scale
Naranjo’s probability scale is the most commonly used
causality assessment method, which has gained popularity among
clinicians because of its simplicity. It is a structured, transparent,
consistent and easy to apply assessment method. The Naranjo’s
criteria classifies the probability that an ADR is related to the
drug therapy based on a list of questions, which examine factors
such as the temporal association of drug administration and event
occurrence, alternative causes for the event, drug levels, dose–
response relationships and previous patient experience with the
medication. The ADRs are assigned to a probability category from
the total score as follows:
• definite if the overall score is 9 or greater,
• probable for a score of 5-8,
• possible for 1-4 and
• doubtful if the score is 0
The Naranjo’s criteria do not take into account drug-drug
interactions. Drugs are evaluated individually for causality, and
points are deducted if another factor may have resulted in the
ADRs, thereby weakening the causal association. The Naranjo
Scale was originally developed to assess the drug and its ADRs
analysis at therapeutic dose. It has not been validated for use
in patients that are critically ill, suffer specific organ toxicity
or overdose. Application of the Naranjo’s Scale in the overdose
setting is not scientifically valid [13-15].
The WHO-UMC causality assessment system
The WHO-UMC system has been developed in consultation
with the National Centres participating in the Programme for
IDM and is meant as a practical tool for the assessment of case
reports. It is basically a combined assessment taking into account
the clinical-pharmacological aspects of the case history and
the quality of the documentation of the observation. Since PV
is particularly concerned with the detection of unknown and
unexpected ADRs, other criteria such as previous knowledge and
statistical chance play a less prominent role in the system. It is
recognised that the semantics of the definitions are critical and
that individual judgements may therefore differ. There are other
algorithms that are either very complex or too specific for general
use. This method gives guidance to the general arguments which
should be used to select one category over another. The various
causality categories are listed in Table.No.2. The assessment
criteria of the various categories are shown in a point-wise way,
as has been developed for practical training during the UMC
Training courses .
WHO-UMC & India
The WHO Program for IDM provides a forum for WHO member
states that include India to collaborate in the monitoring of drug
safety. Within the program, individual case reports of suspected
ADRs are collected and stored in a common database, presently
containing over 3.7 million case reports. Since 1978, the UMC in
Sweden has carried out the Program. The UMC is responsible for
the collection of data ADRs from around the world, especially
from countries that are members of the WHO including India.
Member countries send their reports to the UMC where they are
processed, evaluated and entered into the WHO International
Database. When there are several reports of ADRs to a particular
drug this process may lead to the detection of a signal—an alert
about a possible hazard communicated to member countries.
This happens only after detailed evaluation & expert review.
Figure 2: Suspected Adverse Drug Reaction Reporting Form
Table 2: Causality assessment criteria
• Event or laboratory test abnormality, with plausible time relationship to drug intake
• Cannot be explained by disease or other drugs
• Response to withdrawal plausible (pharmacologically, pathologically)
• Event definitive pharmacologically or phenomenologically
(i.e. an objective and specific medical disorder or a recognised
• Rechallenge satisfactory, if necessary
• Event or laboratory test abnormality, with reasonable time relationship to drug intake
• Unlikely to be attributed to disease or other drugs
• Response to withdrawal clinically reasonable
• Rechallenge not required
• Event or laboratory test abnormality, with reasonable time
relationship to drug intake
• Could also be explained by disease or other drugs
• Information on drug withdrawal may be lacking or unclear
• Event or laboratory test abnormality, with a time to drug intake
that makes a relationship improbable (but not impossible)
• Disease or other drugs provide plausible explanations
• Event or laboratory test abnormality
• More data for proper assessment needed
• Additional data under examination
• Report suggesting an adverse reaction
• Cannot be judged because information is insufficient or contradictory
• Data cannot be supplemented or verified
These ADRs reports are assessed locally and may lead to action
within the country. Through membership of The WHO IDMP, a
country can know if similar reports are being made elsewhere.
(The European Union also has its own scheme.) India is a country
with a large patient’s pool and healthcare professionals, yet ADRs
reporting is in its infancy [17-19].
Pharmacovigilance Programme of India (PvPI)
A National PV Centre is located in the Department of
Pharmacology, All India Institute of Medical Sciences (AIIMS),
New Delhi and two WHO special centres are located in Mumbai
(KEM Hospital) and Aligarh (JLN Hospital). These centres were to
report ADRs to the drug regulatory authority of India. The major
role of these centres was to monitor ADRs to medicines marketed
in India. 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
collaboration with Indian Pharmacopeia Commission (IPC),
Ghaziabad, (U.P.) is initiating a nation-wide PV programme for
protecting the health of the patients by assuring drug safety.
The programme shall be coordinated by the IPC as a National
Coordinating Centre (NCC). The centre will operate under the
supervision of a Steering Committee. The PvPI was initiated by
the Government of India on 14 July 2010 with the AIIMS, New
Delhi as the NCC for monitoring ADRs in the country for safeguarding
Public Health. In the year 2010, 22 ADRs monitoring
centres including the All India Institute of Medical Sciences
(AIIMS) New Delhi, were set up under this programme. To ensure
implementation of this programme in a more effective way, the
NCC was shifted from the AIIMS, to the IPC on 15 April 2011.
The following organizations play a key collaborative role in
the global oversight of PV.
The World Health Organization
The principle of international collaboration in the field of
PV is the basis for the WHO Programme for IDM, through which
over 150 member nations have systems in place that encourage
healthcare personnel to record ADRs of drugs in their patients.
These reports are assessed locally and may lead to action within
the country. Since 1978, the programme has been managed by
the UMC to which member countries send their reports to be
processed, evaluated and entered into an international database
called Vigi-Base. Membership in the WHO Programme enables
a country to know if similar reports are being made elsewhere.
When there are several reports of ADRs to a particular drug, this
process may lead to the detection of a signal, and an alert about
a possible hazard communicated to member countries after
detailed evaluation and expert review [20, 21].
The International Council for Harmonisation (ICH)
ICH is a global organization with members from the European
Union, the United States and Japan; its goal is to recommend global
standards for drug companies and drug regulatory authorities
around the world, with the ICH Steering Committee (SC)
overseeing harmonization activities. Established in 1990, each of
its 6 co-sponsors—the European Federation of Pharmaceutical
Industries and Associations, Japan’s Ministry of Health, Labour
and Welfare, the Japanese Pharmaceutical Manufacturers
Association, the FDA, and the Pharmaceutical Research and
Manufacturers of America—have 2 seats on the SC. Other
parties have a significant interest in ICH and have been invited to
nominate observers to the SC; 3 current observers are the WHO,
Health Canada, and the European Free Trade Association , with
the International Federation of Pharmaceutical Manufacturers
Association participating as a non-voting member of the SC .
The Council for International Organizations of Medical
CIOMS a part of the WHO is a globally oriented think tank
that provides guidance on drug safety related topics through
its Working Groups. The CIOMS prepares reports that are used
as a reference for developing future drug regulatory policy and
procedures, and over the years, many of CIOMS proposed policies
have been adopted. Examples of topics these reports have covered
include: Current Challenges in PV: Pragmatic Approaches (CIOMS
V); Management of Safety Information from Clinical Trials (CIOMS
VI); the Development Safety Update Report: Harmonizing the
Format and Content for Periodic Safety Reporting During Clinical
Trials (CIOMS VII); and Practical Aspects of Signal Detection in
PV: Report of CIOMS Working Group (CIOMS VIII).
The International Society of PV (ISoP)
ISoP is an international non-profit scientific organization,
which aims to foster PV both scientifically, educationally and
enhance all aspects of the safe and proper use of medicines, in
all countries. It was established in 1992 as the European Society
For, the problems & challenges facing the development of a
robust PV system of India, the following proposals might be as
1. Build & maintain a vigorous PV system.
2. Making PV reporting mandatory and introducing PV
3. High-level discussions with various stakeholders.
4. Creating a single country-specific ADRs reporting form to be
used by all.
5. Strengthen the Drug Controller General of India (DCGI) office
with trained scientific and medical assessors for PV.
6. Creating a clinical trial and post-marketing database for SAEs
/ SUSARs and ADRs for signal detection and access to all
relevant data from various stakeholders.
7. Education and training of medical students, pharmacists and
nurses in the area of PV.
8. List all new drugs/indications by maintaining a standard
database for every pharmaceutical company.
9. Collaborating with PV organizations in enhancing drug safety
with advancements in information technology, there has
been the emergence of new opportunities for national and
international collaborations that can enhance post-marketing
surveillance programs and increase drug safety.
10. Building a network of PV and pharmacopeidemiologists in
The PV in India continues to grow, evolve, and improve. India
is the largest producer of pharmaceuticals and now emerging as
an important clinical trial hub in the world. The DCGI has shown
its commitment to ensure safe use of drugs by establishing the
National PV Program. PV may not rely upon one single method,
but needs a strategy of complementary activities. The quality
of the reports can be increased through proper training and retraining
of the personnel engaged in the PV activity. A suitably
working PV system is important if medicines are to be used
prudently. It will be advantageous for healthcare professionals,
regulatory authorities, pharmaceutical companies and consumers
to monitor medicines for risk. Thus, a world class PV system can
definitely be empowered in India.
- WHO. The Importance of Pharmacovigilance: Safety Monitoring of medicinal products. 2002;
- Singh KNM and Kanase HR. Pharmacovigilance Programme of India: The Beginning, Current Status and Recent Progress. Adv Pharmacoepidemiol Drug Saf. 2017;6(4):1-4. Doi: 10.4172/2167-1052.1000219
- Pharmacovigilance. World Health Organization. 2017;
- Kalaiselvan V, Thota P, Singh GN. Pharmacovigilance Programme of India: Recent developments and future perspectives. Indian J Pharmacol. 2016;48(6):624-628. Doi: 10.4103/0253-7613.194855
- PvPI Reaches out to rural masses. Newsletter Pharmacovigilance Programme of India. 2017;
- Pharmacovigilance & Risk Management Strategies Forum. 5th Annual Flemming Conference, Philadelphia, PA. 2018;
- Kenneth FS and David AG. Case-control studies: research in reverse. Lancet. 2002;359(9304):431-434. Doi: 10.1016/S0140-6736(02)07605-5
- Honig PK. Advancing the science of pharmacovigilance. Clin Pharmacol Ther. 2013;93(6):474-475. Doi: 10.1038/clpt.2013.60
- Williams D and Feely J. Underreporting of adverse drug reactions: attitudes of Irish doctors. Ir J Med Sci. 1999;168(4):257-261.
- McBride WG. Thalidomide and congenital abnormalities. Lancet. 1961;278(7216):1358.
- Olsson S. The role of the WHO Programme for International Drug Monitoring in coordinating worldwide drug safety efforts. Drug Saf. 1998;19(1):1-10.
- Edwards IR. The accelerating need for pharmacovigilance. J R Colle Physicians Lond. 2000;34(1):48-51.
- Moore N. The role of the clinical pharmacologist in the management of ADRs. Drug Safety. 2001;24(1):1-7.
- Kulkarni RD. Reporting system for rare side effects of non-narcotic analgesics in India: Problems and opportunities. Medical Toxicology. 1986;1:110-113.
- Gandhi TK, Weingart SN, Borus J, Seger AC, Josh Peterson, Elisabeth Burdick, et al. Adverse drug events in ambulatory care. N Engl J Med. 2003;348:1556-1564. Doi: 10.1056/NEJMsa020703
- World Health Organization (WHO). Uppsala Monitoring Centre: The use of the WHO-UMC system for standardized case causality assessment. 2005;
- Chyka PA and McCommon SW. Reporting of ADRs by poison control centres in the US. Drug Saf. 2000;23(1):87-93.
- Dal Pan GJ. Ongoing challenges in pharmacovigilance. Drug Saf. 2014;37(1):1-8. Doi: 10.1007/s40264-013-0123-x
- Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA. 1998;279915):1200-1205.
- Folb PI and Olliaro P. Pharmaceutical policies and regulatory control. WHO Drug Information. 2000;14(2):82-84.
- Evans SJ. Pharmacovigilance: a science or fielding emergencies?. Stat Med. 2000;19(23):3199-3209.
- Wieniawski W. International harmonization of regulatory activities: future options. WHO Drug Information. 2000;14(3):145-159.