Introduction
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.
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. With a number of recent high-profile drug withdrawals,
like Cerivastatin, the pharmaceutical industry and regulatory agencies have
raised the issue of Pharmacovigilance. Early detection of signals from both
clinical trials and post-marketing surveillance studies have now been adapted
by major pharmaceutical companies in order to identify the risks associated
with the medicinal product and effectively manage the risks by applying robust
risk management plans throughout the lifecycle of the product. Signal detection
and risk management has added a new dimension to the field of Pharmacovigilance
and as an evolving discipline; it requires ongoing refinement in order to
increase its applicability and value to public health.
While major advancements in 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 the importance of Pharmacovigilance and
how it impacts the lifecycle of the product. This will enable integration of
good Pharmacovigilance practice in the processes and procedures to help ensure
regulatory compliance and enhance clinical trial safety and post-marketing
surveillance.
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. Although tested regarding aspect, taste and odor,
its safety was not evaluated before launching. 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.
The thalidomide tragedy is a milestone in the origin and development of
Pharmacovigilance. Thalidomide was introduced in 1957 and widely prescribed as
an allegedly harmless treatment for morning sickness and nausea. It was tested
in approximately 300 patients without toxicity. It 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-
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Harris amendment was approved, requiring scientific evidences of
efficacy and safety before drug tests in humans.
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 center 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.
History of 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
centers, each covering a population of 50 million, was proposed for India.
However, nothing much happened until a decade later when in 1997, India joined
the WHO Adverse Drug Reaction Monitoring Programme based in Uppsala, Sweden.
This attempt was unsuccessful and hence, from 1January 2005, the WHO-sponsored
and World Bank-funded National Pharmacovigilance Program for India was made
operational.
The National Pharmacovigilance Program established in January 2005, was
to be 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), 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. The program has
three broad objectives: the short-term objective is to foster a reporting
culture, the intermediate objective is to involve a large number of healthcare
professionals in the system in information dissemination and the long-term
objective is for the program to be a benchmark for global drug monitoring.
Given this background on Pharmacovigilance in India to date, things have
definitely changed for the better but at a very slow pace. The Regulatory
Authority for India should be commended for introducing and implementing the
Schedule Y and for reporting of all serious adverse events (SAEs) including
suspected unexpected serious adverse reactions (SUSARS) from clinical trials.
However, there is a need of spontaneous adverse event reporting from
post-marketed medicines to the zonal centers and in turn to the National
Pharmacovigilance Centers to the WHO Uppsala Monitoring Center, which at the
moment is woefully lacking.
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Therefore, in these circumstances, the questions that arise are whether
the strategy should be changed and if so, how?
The immensity of the problem of ADRs
A number of studies conducted throughout the world have demonstrated
that ADRs significantly decrease the quality of life, increase
hospitalizations, prolong hospital stay and increase mortality. A landmark
study by Lazarou in 1998 described ADRs to be the fourth to sixth 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 the death of 15 out of 1000
patients admitted. Furthermore, the financial cost of ADRs to the healthcare
system is also huge. With more new medicines being approved for marketing more
quickly without long-term safety studies by the regulatory authorities and
switching of prescription-only medicines (POM) to over-the-counter (OTC) to be
used more widely by patients for self-medication, the general public is at risk
of exposing itself to ADRs.
Current scenario of Pharmacovigilance in India
India is a vast country and there is a surfeit of drug brands-more than
6,000 licensed drug manufacturers and over 60,000 branded formulations. India
is the fourth largest producer of pharmaceuticals in the world and 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.
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.
However, what needs to be more important along with the funding is a
focused vision and effective strategy for developing the Pharmacovigilance
systems, especially in the Drug Controller General of India Office, which is
lacking. Traditionally, Pharmacovigilance was never done in India in
pharmaceutical companies, be it Indian or multinational companies (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,
intertwined with regulations and complex systems. The need is therefore to
engage a completely independent adviser who has extensive and practical
knowledge on Pharmacovigilance, who can act as a Pharmacovigilance Advisor to
the Government of India to effectively implement the systems and policies on
Pharmacovigilance. This will help the DCGI to spearhead the activities and
implementation of Pharmacovigilance.
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The information obtained to date in the zonal centers from various
peripheral centers is often poor and not well-analyzed. There is insufficient
research on ADRs in India, so the exact incidence of specific ADRs is unknown.
The reporting forms used by many people engaged in various Pharmacovigilance
works are different from the reporting form used by the National
Pharmacovigilance Program, which makes it extremely difficult to transfer data
to the national database, even if this has been shared by the various parties.
Understanding by healthcare professionals (both in rural areas and urban
cities and hospitals) and knowledge and motivation for Pharmacovigilance is
almost negligible. There is hardly any encouragement from the department of
health to provide more training and create more awareness amongst them for
better reporting.
In India, there are several consumer groups who encourage patients to
report any adverse reactions encountered by them, although there is no
information for patients on how to report ADRs directly to the regulatory authority.
Direct reports from the patients, the ones who actually experience ADRs, are
not accepted by the monitoring centers and by regulatory authorities. To add to
this is the total lack of any awareness about ADRs in the general population.
With more and more clinical trials and other clinical research
activities being conducted in India, there is an immense need to understand the
importance of Pharmacovigilance and how it impacts the lifecycle of the
product. Given this situation at present, the DCGI should act quickly to
improve Pharmacovigilance so as to integrate Good Pharmacovigilance Practice
into the processes and procedures to help ensure regulatory compliance and
enhance clinical trial safety and post-marketing surveillance.
Strategies and proposals: The way forward in India
A properly working Pharmacovigilance system is essential if medicines
are to be used safely. It will benefit all parties including healthcare
professionals, regulatory authorities, pharmaceutical companies and the
consumers. It helps pharmaceutical companies to monitor their medicines for
risk and to devise and implement effective risk management plans to save their
drugs in difficult circumstances.
Having considered the problems and challenges facing the development of a robust
Pharmacovigilance system for
India, we would like to make the following proposals:
1. Building and maintaining a
robust Pharmacovigilance system
The DCGI should invite experienced private firms to help, train and set
up the Pharmacovigilance system to combat the problems of inexperience and
shortage of trained personnel.
2.
Making Pharmacovigilance
reporting mandatory and introducing Pharmacovigilance inspections
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The Government of India's Health Ministry will need to pass a law and
make Pharmacovigilance reporting mandatory. This should be valid not only for
the MNCs operating within India but also for the Indian pharmaceutical
companies. A department for Pharmacovigilance Inspections should be
incorporated within the DCGI with the view of starting inspections in all
pharmaceutical companies operating in India. All pharmaceutical companies
should be instructed to maintain and submit to the DCGI the Summary of
Pharmacovigilance System document operating within the company, which would
serve as the base for future Pharmacovigilance inspections.
3. High-level discussions with
various stakeholders
A high-level discussion with various stakeholders, i.e., Ministry of
Health and Family Welfare (MHW), Indian Council of Medical Research (ICMR),
Medical Council of India (MCI), Pharmacy Council, Nursing Council, Dental
Council, Pharmaceutical Companies, Consumer Associations, Nongovernmental
Organizations (NGOs) and Patient Groups should be initiated in order to make
them aware of how the DCGI is planning to improve and develop a robust system
in Pharmacovigilance
4.
Strengthen the DCGI office with
trained scientific and medical assessors for Pharmacovigilance
Intensive training should be given in all aspects of Pharmacovigilance
to officials working within the Pharmacovigilance department of the DCGI and in
the peripheral, regional and zonal centers. This should be an ongoing activity
with training scheduled twice a year.
5. Creating a single country wide
specific adverse event reporting form to be used by all
A single countrywide specific adverse event reporting form needs to be
designed, which should not only be used by the National Pharmacovigilance
Centers, but also by all registered hospitals (both private and government),
teaching hospitals, Drug Information Centers and pharmacies throughout the
country. It should also be made available to all primary healthcare centers
(PHCs) in rural areas and all practicing general practitioners and physicians.
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
Full complete data should be made available to the DCGI and to the
various stakeholders from the date of first registration of the clinical trial
in the India. This data should comply with consolidated standards of reporting
trials (CONSORT) guidelines including overall benefit- risk profile of the
product.
Current standards of safety reporting as outlined in Schedule Y and
information about all AEs and ADRs per study arm should be systematically
included as well as detailed description of cases with previously unknown
AEs/ADRs and the reasons for study withdrawals.
For drugs already in the market, type and frequency of all adverse
events (serious and non-serious) should be submitted in periodic safety update
reports (PSURs) and also added to the summary of product characteristics
(SPCs).
7.
List all new drugs/indications by
maintaining a standard database for every pharmaceutical company
A list should be maintained by the regulatory authorities and
pharmaceutical companies for all new drugs/indications in the database. All new
issues need to be put under heightened surveillance. Pharmaceutical companies
in these circumstances should have meetings set up with the DCGI to outline
their risk management plan (RMP) for the safety issues in question and describe
how they would put effective strategies in place to mitigate them.
8.
Education and training of medical
students, pharmacists and nurses in the area of Pharmacovigilance
There are several courses conducted by various organizations focusing in
clinical research, but to date there is no course relevant to Pharmacovigilance
in the country. The various stakeholders including the MCI should incorporate a
Pharmacovigilance syllabus within the pharmacology and medicine curricula so
that proper theoretical and practical training can be imparted to physicians.
Similarly, nurses and pharmacists should also be trained in Pharmacovigilance
so that they are able to recognize ADRs and develop a culture of reporting ADRs
in the future.
An awareness program and a training schedule (both by distance education
and face-to-face learning) covering all aspects of Pharmacovigilance have now
been designed by Symogen Ltd. These are meant for the research and development
(R and D)-based pharmaceutical companies, particularly those involved in new
drug research, the medical profession, the pharmacists and chemist-druggist
trades and the patients, to be alert in detecting ADRs and reporting them to
the Indian regulatory agencies, who in turn will investigate and take timely
corrective action.
9. Collaborating with
Pharmacovigilance organizations in enhancing drug safety
With advancements in information technology (IT), there has been the
emergence of new opportunities for national and international collaborations
that can enhance post-marketing surveillance programs and increase drug safety.
The Uppsala Monitoring Center (UMC) is an example of an international
collaboration to establish a harmonized post-marketing surveillance database.
The system is based on the exchange of adverse reaction information among
national drug monitoring centers in 80 countries. The information is
transferred, stored and retrieved in a timely and secure way through the
internet. The UMC database collectively contains over four million records with
a large number of data fields.
A similar database can be built for the DCGI with the help of
experienced private firms from the safety data received from clinical trials
and post-marketing surveillance.
10. Building a network of
Pharmacovigilance and pharmacopeidemiologists in India
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A core
group of experts will need to be formed which will have representatives from
MNCs, Indian pharmaceutical companies and personnel from the regulatory
authority (DCGI).
11.
Interaction with the IT sector in
building a robust Pharmacovigilance system for India Software programs
developed can be used for collection and analyses of data sets, determining
trends of drug usage in various disease areas, compliance, medication errors
and
drug interactions leading to
ADRs.
The Importance of Pharmacovigilance
A critical examination of the strengths and weaknesses of present
systems of safety monitoring, in order to increase their impact, and an
overview of the challenges facing Pharmacovigilance in the future.
•
Involvement in Drug Safety Monitoring by WHO
•
Partners in Pharmacovigilance
•
Pharmacovigilance in Drug Regulation
•
Pharmacovigilance in Clinical Practice
•
Pharmacovigilance in International Health
•
Considerations for the Future
The purpose of Pharmacovigilance
Pharmacovigilance is the science and activities relating to the
detection, assessment, understanding and prevention of adverse effects or any
other possible drug-related problems. Recently, its concerns have been widened
to include:
•
herbals
•
traditional and complementary medicines
•
blood products
•
biologicals
•
medical devices
•
vaccines.
Many other issues are also of
relevance to the science:
•
substandard medicines
•
medication errors
•
lack of efficacy reports
•
use of medicines for indications
that are not approved and for which there is inadequate scientific basis
•
case reports of acute and chronic poisoning
•
assessment of drug-related mortality
•
abuse and misuse of medicines
•
adverse interactions of medicines with chemicals,
other medicines, and food.
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•
improve patient care and safety
in relation to the use of medicines and all medical and paramedical
interventions,
•
improve public health and safety in relation to the
use of medicines,
•
contribute to the assessment of
benefit, harm, effectiveness and risk of medicines, encouraging their safe,
rational and more effective (including cost-effective) use, and
•
promote understanding, education
and clinical training in Pharmacovigilance and its effective communication to
the public.
Pharmacovigilance has developed and will continue to develop in response
to the special needs and according to the particular strengths of members of
the WHO Program and beyond. Such active influence needs to be encouraged and
fostered; it is a source of vigour and originality that has contributed much to
international practice and standards.
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