This chapter introduces the events and ideas that have underpinned the foundation and early development of pharmacovigilance over the last thirty years under the aegis of the World Health Organization. In 2002, more than 65 countries have their own pharmacovigilance centres. Membership of the WHO Programme for International Drug Monitoring is co-ordinated by the WHO Collaborating Centre for International Drug Monitoring, known as the Uppsala Monitoring Centre (UMC).
The evolution of pharmacovigilance in recent years and its growing importance as a science critical to effective clinical practice and public health science are described. The national pharmacovigilance centres have become a significant influence on the drug regulatory authorities, at a time when drug safety concerns have become increasingly important in public health and clinical practice. Pharmacovigilance is now firmly based on sound scientific principles and is integral to effective clinical practice. The discipline needs to develop further to meet public expectations and the demands of modern public health.
According to Article 2 of its constitution, the World Health Organization has a mandate from its Member States
to develop, establish, and promote international standards with respect to food, biological, pharmaceutical and similar products
There is also provision made in Article 21 of the constitution of the World Health Assembly to adopt regulations concerning
standards with respect to the safety, purity and potency of biological, pharmaceutical and similar products moving in international commerce.
It was not until the disaster caused by thalidomide in 1961 that the first systematic international efforts were initiated to address drug safety issues. At that time many thousands of congenitally deformed infants were born as the result of exposure in utero to an unsafe medicine promoted for use by pregnant mothers. The Sixteenth World Health Assembly (1963) adopted a resolution (WHA 16.36)(1) that reaffirmed the need for early action in regard to rapid dissemination of information on adverse drug reactions and led, later, to creation of the WHO Pilot Research Project for International Drug Monitoring in 1968. The purpose of this was to develop a system, applicable internationally, for detecting previously unknown or poorly understood adverse effects of medicines. A WHO technical report followed based on a consultation meeting held in 1971.(2)
From these beginnings emerged the practice and science of pharmacovigilance. Systems were developed in Member States for the collection of individual case histories of ADRs and evaluation of them. The collection of international ADR reports in a central database, would serve the important function of contributing to the work of national drug regulatory authorities, improve the safety profile of medicines, and help avoid further disasters.(3)
From pilot to permanence
The principal achievement of the 1971 WHO consultation meeting was:
• to advocate establishment of national centres for drug monitoring,
• to provide guidelines
• to identify the contribution that national centres might make to the international system.
In so doing, it was envisaged that the time necessary to recognize that a drug produces an adverse reaction might be reduced, and the importance of the reaction more readily assessed. It was noted that
• data collection from health practitioners,
• systematic monitoring of populations,
• review of health statistics and of drug utilization data, and
• effective analysis of input data
would be necessary for the objectives of pharmacovigilance to be achieved. Special attention would need to be paid to new drugs. Specialized reference centres would be required to provide additional data to National Centres and for investigation of particular drug safety problems.
Since the start of the International Programme in 1968 much has been accomplished:
• The pilot project has developed into the WHO Programme for International Drug Monitoring now co-ordinated by the Uppsala Monitoring Centre (UMC) in Uppsala, Sweden, with oversight by an international board
• The Programme has expanded to include more than sixty member countries
• In many countries, regional reporting centres, interest groups, dedicated internal medicine and pharmacology department units, drug and poison information centres and other non-governmental organizations have developed
• The idea that pharmacovigilance centres are a luxury, affordable only in the developed world, has been replaced by a realization that a reliable system of pharmacovigilance is necessary for public health and for the rational, safe and cost-effective use of medicines in all countries. Where no established regulatory infrastructure exists, a drug monitoring system is an effective and cost-efficient means of detecting and minimizing injury to patients and averting potential disaster.
The creation of the International Society of Pharmacoepidemiology (ISPE) in 1984 and of the European Society of Pharmacovigilance (ESOP - later ISoP - the International Society) in 1992 marked the introduction of pharmacovigilance formally into the research and academic world, and its increasing integration into clinical practice. Specialist medical journals have appeared, and a number of countries have implemented active surveillance systems to complement conventional methods of drug monitoring. Examples of such systems are:
• the prescription event monitoring systems (PEM) in New Zealand and the United Kingdom
• record linkage systems in the United States of America and Canada
• case control studies in the United States of America.
Pharmacovigilance activities have also evolved as a regulatory activity. In the early 1980s, in close collaboration with the WHO, the Council for International Organizations of Medical Sciences (CIOMS) launched its programme on drug development and use. CIOMS provided a forum for policy makers, pharmaceutical manufacturers, government officials and academics to make recommendations on the communication of safety information between regulators and the pharmaceutical industry. The adoption of many of the recommendations of CIOMS by the International Conference on Harmonization (ICH) in the 1990s has had a notable impact on international drug regulation.
Within the last decade, there has been a growing awareness that the scope of pharmacovigilance should be extended beyond the strict confines of detecting new signals of safety concerns. Globalization, consumerism, the explosion in free trade and communication across borders, and increasing use of the Internet have resulted in a change in access to all medicinal products and information on them. These changes have given rise to new kinds of safety concerns such as:
• illegal sale of medicines and drugs of abuse over the Internet
• increasing self-medication practices
• irrational and potentially unsafe drug donation practices
• widespread manufacture and sale of counterfeit and substandard medicines
• increasing use of traditional medicines outside the confines of the traditional culture of use
• increasing use of traditional medicines and herbal medicines with other medicine with potential for adverse interactions.
There is a need for a reconsideration of pharmacovigilance practice in the light of the lack of clear definition of boundaries between:
• medicines (including traditional medicines, herbal medicines and ‘natural products’),
• medical devices, and
Increasing public expectation of safety in relation to all of these adds another dimension of pressure for change. National pharmacovigilance centres are in no position to address all these safety concerns on their own, but they are especially able to detect and anticipate the impact of such problems on the safety of patients. Through strong links with the national drug regulatory authority as well as to other countries, National Centres are in a position to influence decision-making on drug and other health-related policies.
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:(4)
• traditional and complementary medicines
• blood products
• medical devices
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.(5)
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 Programme 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.