Adverse drug reactions (ADRs) are considered as one among the leading causes
of morbidity and mortality.
According to WHO, Adverse Drug Reaction is any noxious, unintended,
and undesired effect of a drug, which occurs at doses used in humans for prophylaxis,
diagnosis, or therapy. Pharmacovigilance is an important and integral part of
clinical research. While major advancements of the discipline of pharmacovigilance
have taken place in the West, not much has been achieved in India. However,
with more clinical trials and clinical research activity being conducted in
India, there is an immense need to understand and implement pharmacovigilance.
For this to happen in India, the mind set of people working in regulatory agency
(DCGI ) and the Indian pharmaceutical companies need to change.
The number of
Adverse Drug Reactions (ADRs) reported have also
resulted in an increase in the volume of data handled and to understand
pharmacovigilance a high level of expertise is required to rapidly detect drug
risks as well as to defend the product against an inappropriate removal.
The way drugs are being monitored has changed, both internationally as well as on the
national level. Both clinical trials safety and postmarketing
pharmacovigilance are critical throughout the product life cycle1. Pharmacovigilance
is defined as the pharmacological science relating to the detection,
assessment, understanding and prevention of adverse effects, particularly
long-term and short-term adverse effects of medicines.2 With a
number of recent high-profile drug withdrawals, the pharmaceutical industry and
regulatory agencies have raised the bar. Early detection of signals from both
clinical trials and postmarketing surveillance
studies have now been adapted by major pharmaceutical companies in order to
identify the risks associated with the medicinal product and effectively
managing the risks by applying robust risk management plans throughout the life
cycle of the product ADR reporting programs encourage ADR surveillance, promote
the reporting of ADRs and stimulate the education of
health professionals regarding potential ADRs.3 Spontaneous reporting program, a common method of drug surveillance is capable of recognizing ADRs in the daily medical practice,
even though underreporting and absence of information on number of people
actually exposed to the drug are its disadvantages. Unfortunately, in spite of
presence of five well organized centres for drug
monitoring in the country, the numbers of reports sent annually are dismal.
ADRs account for 2.1% of hospital admissions, with 39.3% of
them are life threatening.4 Therefore, in order to strengthen the
field of pharmacovigilance various strategies need to be developed and this
should include but should not be limited to; building a robust
pharmacovigilance system, making reporting mandatory, creating a single
nationwide reporting form and a database of all the adverse events.
Need For Pharmacovigilance
Phase IV of the evaluation of a drug starts when the
marketing license is granted and extends over many years. It consists of pharmacoepidemiological studies to evaluate the
effectiveness, safety, and utilization of the drug in large populations, under
real-life conditions. The results confirm or disprove the effectiveness of the
drug in clinical practice (confirmation of the therapeutic effect), determine
whether approved uses should be expanded or restricted, any untoward
interactions (pharmacovigilance) and pharmacoeconomics
of the drugs.
Major aims of pharmacovigilance5-7 are:
1. Early detection of hitherto unknown adverse reactions and interactions
2. Detection of increases in frequency of (known) adverse reactions
3. Identification of risk factors and possible mechanisms underlying adverse reactions
4. Estimation of quantitative aspects of benefit/risk analysis and dissemination of
information needed to improve drug prescribing and regulation.
The ultimate goals of pharmacovigilance are:
- The rational and safe use of medical drugs.
- The assessment and communication of the risks and benefits of drugs on the market.
- Educating and informing of patients.
National Pharmacovigilance Program
Even though pharmacovigilance is still in its infancy, it 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.
However, nothing much happened until a decade later when in
1998, India joined the World Health Organization (WHO) Adverse Drug Reaction
Monitoring Programme based in Uppsala, Sweden.8
The program has three-tier structure- 2 zonal centers 5
regional centers and various peripheral centers. Pharmacovigilance centers
pursue four objectives: to detect ADRs, to evaluate
them, to study them what is the difference between evaluate and study?, and to
inform prescribing physicians.
The Central Drugs Standard Control Organization (CDSCO)
launched the National Pharmacovigilance Program in November 2004 under the
aegis of Directorate General of Health Services, Union Ministry of Health and
Family Welfare. The basic purpose of this program is to collate, analyze and
archive adverse drug reaction data for making regulatory decisions regarding
drugs marketed in India. The National Pharmacovigilance Programme
will have the following goals:
- To foster a culture of notification
- To engage several healthcare professionals and NGOs in the drug monitoring and
information dissemination processes.
- To achieve such operational efficiencies that would make Indian National
Pharmacovigilance Programme a benchmark for
global drug monitoring endeavours.
The programme shall be coordinated
by the National Pharmacovigilance Centre at CDSCO, New Delhi. The National
Centre will operate under the supervision of the National Pharmacovigilance
Advisory Committee to recommend procedures and guidelines for regulatory interventions.
Specific objectives of the Programme:
- To create an ADR database for the Indian population
- To create awareness of ADR monitoring among people
- To ensure optimum safety of drug products in Indian market
- To create infrastructure for ongoing regulatory review of PSURs
(periodic safety update reports)
Noteworhty Features And Operation Of NPP
The national pharmacovigilance center at CDSCO will undertake
the following activities:
1)Shall monitor the adverse drug reactions of
medicines in order to identify previously unexpected adverse drug reactions or
indicate that certain reactions occur more commonly than previously believed. This
information will then be keyed into the ADR database for use in aggregate
analysis. These reports shall also be submitted to the WHO International Drug
Monitoring Programme for international collaboration
on drug safety.
2)Shall review Periodic Safety Update Reports (PSURs) submitted by pharmaceutical companies.
3)Shall maintain contacts with international regulatory bodies working in pharmacovigilance and exchange information on drug safety.
4)Shall assess the regulatory information relating
to safety in order to determine what action, if necessary, needs to be taken to
improve safe use. Based on the available data, the Advisory Committee shall
make recommendations on product label amendments, product withdrawals and
The programme recommends mandatory reporting of :
- ALL adverse events suspected to have been caused by new drugs and ‘Drugs of current
interest’ (List to be published by CDSCO from time to time)
- ALL suspected drug interactions
- Reactions to any other drugs which are suspected of significantly affecting a patient's
management, including reactions suspected of causing:
Death, life-threatening (real risk of dying),
hospitalisation (initial or prolonged), disability
(significant, persistent or permanent), congenital anomaly, required
intervention to prevent permanent impairment or damage.
The physician, nurses or pharmacists are
responsible for reporting and completing the prescribed adverse drug reaction
reporting form. After completing the form, the same may be forwarded to the
nearest peripheral pharmacovigilance center. The latter, in strict confidence,
forward the report to regional center which then perform the causality analysis
which in turn is submitted to zonal center. The data will be statistically
analyzed and forwarded to the global Pharmacovigilance Database managed by WHO
Uppsala Monitoring Centre in Sweden. The final report based on the analysed data will be periodically reviewed by the National
Pharmacovigilance Advisory Committee constituted by the Ministry of Health and
The activities with which various centers are endorsed with includes but are not limited to:
· Zonal centers coordinate the nationwide program
and provides for the facilities like a PC with internet facility, access to
fax, telecom, etc. [AIIMS for North and East and KEM-Mumbai for South and
West]. Other activities includes:
a. to collate the data (approx. 1000-1200 forms) received from RPCs.
b. to verify / validate the causality analysis.
c. to prepare MIS reports for NPC in a specified format.
d. to pass on the final data to WHO Uppsala Centre for their global data pool.
e. to publish a periodic newsletter.
· Regional Centers will undertake the following activities:
a. to collate and scrutinize the data received
b. to perform the causality analysis of all 120 to 150 forms received every month.
c. to submit a monthly report – prepared in a specific form to be forwarded to National
Pharmacovigilance Centre (NPC) every month.
d. to report any alarming or critical ADRs to NPC along with supporting evidence.
· Peripheral centers (ideally medical institutions
in each state and Union territory) to record at least 30 events each month
(statistically speaking 30 events in about 1500 patients who visit each month would
be quite easy to record). Completed event forms shall be forwarded to the
concerned regional centers at the end of each month.
Challenges To The Program
A landmark study 1998 described ADRs to be the 4th-6th largest cause of death
in the USA and ADRs are estimated to cause 3-7% of all hospital admissions.
More than half of these ADRs are not recognized by the physicians on admission
and ADRs may be responsible for death of 15 of 1000 patient’s admitted.9
Furthermore, the financial cost of ADRs to the healthcare system is also huge.
In recent years, however, the lag between when a drug is placed on 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.10 Traditionally, pharmacovigilance was never done in
India in Pharmaceutical companies, be it Indian or MNCs, so there is an immense
shortage of knowledgeable people who will be able to advice the DCGI on this
matter, as pharmacovigilance is a very complex subject, interwined with regulations
and complex systems. India is the fourth largest producer of pharmaceuticals
in the world and is also emerging as a clinical trials hub.11 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. The problem areas which have
identified in India includes:
·Lack of organization and funding of pharmacovigilance systems
· Extreme shortage of qualified trained people to handle pharmacovigilance within the DCGI.
· Information obtained to date in the zonal
centers from various peripheral centers is often poor and not well analyzed
because of insufficient research on ADRs in India.
·Understanding, knowledge and motivation by healthcare professionals is almost negligible.
Recommendations For The Future
Various stakeholders can help the program achieve its objectives comprehensively:
1) Involve professional organizations of healthcare
providers to educate their members about the program and there by sustain their
2) Making pharmacovigilance reporting mandatory and introducing pharmacovigilance
3) Employing trained scientific and medical assessors for pharmacovigilance to strengthen the DCGI office.
4) In addition to the CDSCO website, use newsletters and pamphlets to inform healthcare providers about the
5) Recognize the contribution of notifiers and centers with consistent high
quality performance through citation on the website and in the newsletter to
help motivate everyone to report adverse events.
6)Creating a clinical trial and postmarketing database for serious ADRs 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
pharmacovigilance and building a network of pharmacovigilance and pharmacopeidemiologists in India.
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. Though pharmacovigilance is
still in its infancy in India, this is likely to expand in the times to come.
This is because, as the newer and newer drugs hit the market, the need for pharmacovigilance
grows more than ever before. Physicians should report death due to drugs, life
threatening complications, hospitalization (initial or prolonged), disability
if significant, persistent, or permanent, congenital anomalies, a reaction
which requires medical intervention to prevent damage.
For this, students (both undergraduates and postgraduates) need to be trained
in drug safety and a habit of rational drug use should be inculcated in them
from the beginning. Continuing medical education programmes for physicians and
other health professionals should be conducted to make them aware of the methodologies
and other technical aspects of the drug monitoring process. 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. The only private company,
Symogen Ltd., that deals with all aspects of pharmacovigilance has also started
functioning in India.
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Delhi Institute of Pharmaceutical Education and Research (DIPSAR), New Delhi,India
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