HISTORY
AND DEVELOPMENT OF PHARMACOVIGILANCE
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-
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.
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.
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
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
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.
The specific aims of
Pharmacovigilance are to:
•
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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