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According to WHO Pharmacovigilance is defined as 'the

pharmacological science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.
The etymological roots are: pharmakon (Greek), drug; and

vigilare (Latin), to keep awake or alert, to keep watch.

Pharmacovigilance an umbrella term used to describe the

processes for monitoring and evaluating ADRs is a key component of effective drug regulation systems, clinical practice and public health programs.

It is the study of the safety of marketed drugs examined under the

practical conditions of clinical use in large communities.


No drug which is pharmacologically effective is without hazard.

Furthermore not all hazards can be known before a drug is marketed.

Once put onto the market, a medicine leaves the secure and

protected scientific environment of clinical trials and is legally set free for consumption by the general population.
Experience has shown that many adverse effects, interactions (i.e.

with foods or other medicines) and risk factors come into light only years after release of the drug.

Registration of New Chemical Entities was very

much dependant on the status of products in the reference countries Changes to product information was mainly industry driven Few pre-clinical studies conducted in the region and hardly any Phase IV studies Adverse drug reaction reporting was very minimal and mainly involved reports submitted by health care professionals


Most reports were for known reactions involving

older drugs which were used in government-run hospitals Signal detection not possible as there were too few reports Only able to detect some quality defects of generics which manifested as ADRs Pharmacovigilance was mainly about getting ADR reports and submitting them to WHO No significant regulatory changes made based on these reports


Thalidomide was introduced in 1957, widely prescribed as a

harmless treatment for morning sickness and nausea. It was soon linked to a congenital abnormality which caused severe birth defects in children of women who had been prescribed this medicine during pregnancy. By 1965, thalidomide had been removed from the market in most countries. Nevertheless, it continued to be used for the treatment of leprosy, and in more recent years, its indications have been extended to a much wider range of medical conditions. These uses are allowed only under strict supervision and specialist advice. Despite these precautions, between 1969 and 1995, 34 cases of thalidomide embryopathy were registered in leprosy endemic areas in South America.

The Aims of Pharmacovigilance

To improve patient care and safety

To improve public health and safety

To contribute to the assessment of benefit, harm,

effectiveness and risk of medicines To promote understanding, education and clinical training

Who are the partners?

Government Industry Hospitals and academia Medical and pharmaceutical associations Poisons information centers Health professionals Patients Consumers Media WHO

Current Methods of Pharmacovigilance

Pharmacovigilance is a branch of pharmacoepidemiology but is

restricted to the study, on an epidemiological scale, of drug events or adverse reactions. The success or failure of any pharmacovigilance activity depends on the reporting of suspected adverse reactions. Public health surveillance methods are used to identify new signals of possible ADRs. Studies in pharmacoepidemiology are intended to be either hypothesis-generating or hypothesis-testing. Hypothesis-generating studies, with a recently marketed drug, aim to detect unexpected ADRs. Hypothesis-testing studies aim to prove whether any suspicions that may have been raised are justified.

Hypothesis-generating studies Hypothesis-testing studies

Spontaneous ADR Reporting Prescription Event Monitoring (PEM) Other HypothesisGenerating Methods

Case-control & CaseCrossover studies Cohort studies Randomized Controlled studies

Hypothesis-Generating Studies Spontaneous ADR Reporting Prescription Event Monitoring (PEM) 1. Spontaneous ADR Reporting: Spontaneous Reporting is defined as A system whereby case reports of adverse drug events are voluntarily submitted by health professionals and pharmaceutical companies to the national pharmacovigilance centre. Doctors (in some countries, other healthcare professionals and patients as well) are provided with forms upon which they can notify a central authority of any suspected ADRs that they detect. In the United Kingdom, the yellow card has been used for this purpose since 1964. The blue card system is used in Australia and Malasia. In the United States, the MedWatchform is used and is made broadly available to health professionals to encourage reporting.

The great strength of spontaneous reporting is that it operates for all

drugs throughout the whole of their lifetime; it is the only affordable method of detecting really rare ADRs. The main weaknesses are that there is gross under-reporting, and the data provide a numerator (the number of reports of each suspected reaction) only. 2. Prescription Event Monitoring (PEM): This monitoring is conducted in the United Kingdom and New Zealand, represents a hybrid method, combining aspects of public health surveillance and spontaneous reporting with aspects of formal epidemiological studies. In UK, within British National Health Service (NHS), prescriptions written by general practitioners are sent, once they have been dispensed, to a central Prescription Pricing Authority (PPA). The PPA provides confidential copies of certain prescriptions for newly introduced drugs that are being monitored to the Drug Safety Research Unit (DSRU) at Southampton.

Six or twelve months after the first prescription for an individual drug

in an individual patient, the DSRU sends a green form questionnaire to the general practitioner who wrote the original prescription. Thus, the prescriptions provide the exposure data showing which patients have been exposed to the drug being monitored, and the green forms provide the outcome data showing any events noted during the period of monitoring. The great strengths of this method are that it provides a numerator (the number of reports) and a denominator (the number of patients exposed), both being collected over a precisely known period of observation. The main weakness of PEM is that only 50%70% of the green forms are returned. In addition, because PEM limits follow-up to 6 or 12 months, it cannot identify events of long latency.

3. Other Hypothesis-Generating Methods: In some cases, data being collected for general public health surveillance, such as cause of death files, cancer registries & birth defect registries are used to identify patterns of events that might be associated with medication use. Other methods such as Case-control surveillance Analytical methods & Data mining techniques are being applied to spontaneous reporting databases, databases on potential drug abuse and diversion and large population-based health records.

Hypothesis-Testing Methods:
Case-control and Case-Crossover studies Cohort studies Randomized Controlled studies

1. Case-control and Case-Crossover studies: Studies of this type compare cases with a disease with controls susceptible to the disease but free of it. Using this method, the research compares the exposure rate in the cases with the exposure rate in the controls, adjusting statistically for factors that may confound the association. Casecontrol studies are more efficient than cohort studies, because intensive data need only be collected on the cases and controls of interest.
The casecrossover design is a design very useful for the evaluation of

events with onset shortly after treatment initiation. In this design, cases, but not controls, are identified. A drug association is evaluated through comparing frequency of exposure at the time of the event with frequency of exposure at a different time for the same individuals. This design is less subject to bias than casecontrol studies because individuals serve as their as their own controls.

2. Cohort Studies: These are the studies which start by identifying a particular population with a common characteristic (i.e. a cohort), often based on use of a specific drug and follows them forward in time until some individuals have developed the disease of interest. These studies involve a large body of patients followed up for long enough to detect the outcome of interest. Cohort studies generally include an exposed and unexposed group, but there are also single exposure, disease or general population follow-up studies and registries. An advantage of the cohort study is its ability to quantify both an absolute risk and a relative risk. Cohort studies can be conducted prospectively, but such studies are usually expensive and time-consuming. Retrospective cohort studies can be conducted within large existing databases, providing the advantage of the cohort study design and the efficiencies inherent in studies using existing records. Cohort studies are useful when the outcome has not already been identified or when multiple outcomes are of interest.

3. Randomized Controlled Trials: In this method of study, a group of patients is divided into two in strictly random order; one group is then exposed and the other not exposed, so that the outcomes can be compared. The method is of great importance because random assignment of treatment removes some of the biases possible in observational studies. It is of only limited (but important) use as a pharmacoepidemiological tool because most serious ADRs are relatively uncommon; randomized controlled trials (RCTs) used in such contexts can become unmanageably large and expensive.

New drug in market

A new medicine must pass three hurdles before its approval by

the national drug regulatory authority. Sufficient evidence is required to show the new drug to be 1. of good quality, 2. effective, and 3. safe for the purpose or purposes for which it is proposed. Whereas the first two criteria must be met before any consideration can be given to approval, the issue of safety is less certain. Safety is not absolute, and it can be judged only in relation to efficacy, requiring judgment on the part of the regulators in deciding on acceptable limits of safety.

There is a possibility that rare yet serious adverse

events (such as those occurring with a frequency of, say, one in five thousand) will not be detected in the pre-registration development of the drug. For example, fatal blood dyscrasia occurring in 1 in 5,000 patients treated with a new drug is only likely to be recognized after 15,000 patients have been treated and observed, provided that the background incidence of such a reaction is zero or a causal association with the drug is clear.

Malaria: an example of pharmacovigilance in public health.

In view of the increasing resistance to existing antimalarial medicines, several countries have switched to using combinations of various artemisinin derivatives as their first- and second-line treatments for malaria. The change to artemisinin combination therapies (ACTs) has provided a timely opportunity to introduce a pharmacovigilance system in those countries that hitherto had no established systems for safety monitoring of medicines. In 2003,participants from five African countries were trained in the basic methods of medicine safety monitoring with a view to facilitating the introduction of a common system of pharmacovigilance for new antimalarial treatments. Since then two of these countries have formally established a pharmacovigilance centre; the others are also making progress in monitoring antimalarials.

Pharmacovigilance in practice: The example of cerivastatin

Cerivastatin was first approved as a lipid-regulating agent in

1997. By 2000 a total of 549 cases of rhabdomyolysis associated with cerivastatin use had been reported to the WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden. Consequently a signal was issued regarding an association between cerivastatin,myopathy and rhabdomyolysis. In November 1999 in the United States, and in March 2000 in Canada, prescribing information was changed to include a contraindication for the combined use of cerivastatin and gemfibrozil, another lipid-regulating medicine. A similar action was taken in Australia in February 2001, and a warning issued to alert prescribers to the possibility of rhabdomyolysis occurring with all statins. In June 2001 Europe-wide regulatory action was taken to contraindicate the combined use of cerivastatin and gemfibrozil. On 8 August 2001, the manufacturer voluntarily withdrew cerivastatin from the market on the grounds of an increased risk of rhabdomyolysis, particularly when used in combination with gemfibrozil.

Key Elements Of Pharmacovigilance In National Drug Policy

Establishment of national pharmacovigilance systems for the reporting of adverse events, including national and, if appropriate, regional pharmacovigilance centres. Development of legislation/regulation for medicine monitoring. National policy development (to include costing, budgeting and financing). Continuing education of health-care providers on safe and effective pharmacotherapy. Provision of up-to-date information on adverse reactions to professionals and consumers. Monitoring the impact of pharmacovigilance through process indicators and outcome.

Pharmacovigilance In Clinical Practice

Safety monitoring of medicines in common use should be

an integral part of clinical practice. The degree to which clinicians are informed about the principles of pharmacovigilance, and practice according to them, has a large impact on the quality of health care. Education and training of health professionals in medicine safety, exchange of information between national pharmacovigilance centres, the coordination of such exchange, and the linking of clinical experience of medicine safety with research and health policy, all serve to enhance effective patient care. A regular flow and exchange of information in this way means that national pharmacovigilance programmes are ideally placed to identify gaps in our understanding of medicine-induced diseases.

Good Pharmacovigilance Practice

Effective pharmacovigilance relies on contributions by many people

with varying educational backgrounds. To attain a coherent pharmacovigilance system it is most important that guidelines and standards are developed, which describe the practical details of the intended information flow. Such standard operating procedures should include information on the following:
What constitutes a reportable adverse reaction? Who is expected to report an observation of a suspected medicine

related problem? The availability and practicalities of filling in a reporting form. Procedures for submission or collection of reports. Routines for assessment, follow-up and processing of case reports at the pharmacovigilance centre. Good communication practices.

Assessment of the pharmacovigilance system

Evaluation and assessment should be built into the monitoring

system. The national pharmacovigilance centre, coordinator and review panel should periodically evaluate whether, or to what extent:
the reporting is complete, timely and accurate; response has been swift enough; case management has been appropriate; and action has been appropriate to avoid programme error.

Current progress in pharmacovigilance is marked by increasing use

of databases and by attempts to make the process more proactive and organized. Attempts are being made to augment the spontaneous, random nature of the generation of pharmacovigilance data and to make the process more systematic and structured. There has been a coming together of academic, regulatory and industrial interests across many countries to produce the guidance documents mentioned above as well as good practice guidelines for the conduct of pharmacoepidemiology studies. Health ministries, health professionals and the public can all be reassured by knowing that there is a competent and functional system in place that focuses on the safety of medicines used in the prevention anpld treatment of disease, including vaccines and pharmaceuticals for family planning.