Drug Safety
Under the WHO definition, pharmacovigilance is the science and practical activity related to detecting, assessing, interpreting and preventing adverse consequences of pharmacotherapy or any other problem related to medical intervention.
Modern drugs allow us to fight diseases effectively. However, despite their benefits, adverse drug reactions (ADRs) — common causes of illness, disability and even death — continue to accumulate. In some countries, ADRs are among the ten leading causes of death. Individual patients may show special and unpredictable sensitivity to certain drugs, and when multiple drugs are prescribed there is always a risk of negative drug-drug interactions. Choosing the most effective and safe drug(s) for a given patient therefore requires specific knowledge and skills from the practitioner. Pharmacotherapy’s importance lies in the mechanism for evaluating and monitoring drug safety during clinical use. In practice this means a well-organized pharmacovigilance system. Pharmacovigilance is a key component of effective drug-regulation and public-health systems.
Why pharmacovigilance is needed. Processes related to clinical drug development are shown in the figure.
The clinical evaluation of a drug justifies its free use by the public. At this stage most drugs are tested for safety and efficacy in a limited number of carefully selected people for a short time — between 500 and 5,000 subjects before market entry.
New, medically unproven treatments must also be monitored for efficacy and safety in real-world use. After a drug reaches the pharmacy network, specialists need information on its use in specific population groups (children, pregnant women, the elderly), on efficacy and safety under regular use, especially in combination with other drugs.
Experience shows that many ADRs and drug interactions (including food interactions) may appear years later (Table 1).
Adverse drug reaction: the thalidomide case. Thalidomide was introduced into clinical practice in 1957. It was prescribed without restriction as a supposedly harmless drug for morning sickness during pregnancy. Soon it was linked to congenital malformations in children of women who took it during pregnancy. By 1965 thalidomide had been withdrawn in most countries; it continued to be used only for leprosy. In recent years its approved uses have expanded. The drug is allowed only under strict medical supervision and after consultation with specialists. Despite these precautions, 34 cases of thalidomide-induced embryopathy were found between 1969 and 1995 in a joint Latin American study of birth defects in areas endemic for leprosy.
Pharmacovigilance objectives. The thalidomide tragedy shows the importance of effective drug-monitoring systems. Main objectives: • improve the quality of medical care for patients; • strengthen drug safety; • evaluate the benefit/risk ratio, efficacy and safety of drugs, encourage their rational use including cost considerations; • clinical training of medical specialists in pharmacovigilance and public information on the topic.
Pharmacovigilance partners. Managing drug-related risks requires close, effective cooperation among key pharmacovigilance stakeholders. Difficulties often include lack of resources, political support and, especially, a scientific-technical base. Addressing these issues is a prerequisite for developing the scientific and practical principles of a pharmacovigilance system.
Drug safety monitoring — key partners • Government • Industry • Medical institutions • Medical and pharmaceutical associations • Poison and drug information centers • Medical specialists • Patients • Consumers • Media • World Health Organization
Pharmacovigilance and drug-regulation. A reliable regulatory system lays the foundation for national drug-safety principles and for public trust. To be effective, drug regulators must address a broad range of issues when approving new drugs, including: • clinical-trial conduct; • drug, vaccine and biologics safety issues; • interaction among all stakeholders and effective functioning, especially in crisis situations.
Pharmacovigilance in action: the cerivastatin case. Cerivastatin was introduced as a lipid-regulating drug in 1997. By 2000 the WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden, had received 549 reports of acute rhabdomyolysis linked to cerivastatin. Warnings followed that cerivastatin causes myopathy and acute rhabdomyolysis. In November 1999 in the US and March 2000 in Canada prescribing information was changed — a contraindication against combined use with gemfibrozil. Australia acted similarly in February 2001; doctors were warned of the risk of rhabdomyolysis with statins. In June 2001 Europe-wide measures were adopted with a contraindication against the cerivastatin + gemfibrozil combination. On August 8, 2001 the manufacturer withdrew the drug.
Pharmacovigilance in clinical practice. Drug-safety monitoring must be an integral part of clinical practice everywhere. Care quality depends heavily on clinicians’ awareness of pharmacovigilance principles. Improvement comes through education and training of medical specialists, information exchange between national centers, coordination of these interactions, and alignment of clinical drug-safety experience with research and healthcare policy. Regular flow of information means national pharmacovigilance programs have an ideal opportunity to detect gaps in our understanding of drug-induced diseases.
Pharmacovigilance in disease-control programs. In countries without a drug-regulation or safety-monitoring system, or in remote areas with weak epidemiological surveillance or healthcare infrastructure, these issues are particularly pronounced — especially for drugs used in specific populations, e.g. for malaria, leishmaniasis, schistosomiasis, HIV/AIDS and tuberculosis. In such countries, pharmacovigilance should be prioritized.
Malaria — a public-health pharmacovigilance example. Because of growing resistance to existing antimalarials, some countries are using artemisinin-based combinations (ACT) as first- and second-line therapy. ACT creates an opportunity for timely introduction of pharmacovigilance systems in countries that lacked safety-monitoring systems. In 2003 representatives of five African countries were trained in basic drug-safety monitoring. Since then these countries have made progress in monitoring antimalarial use.
Communicating pharmacovigilance results. Satisfying specialists with the drug-safety evidence is not enough. Equally important is the public’s perception of risks. How safe is “safe enough”? What are acceptable risk levels? Physicians must consider these questions when prescribing. Pharma companies and healthcare authorities are obliged to inform the public about possible risks. Communication methods are in Table 2.
Another method is the use of medical journals and websites. The method depends on urgency and seriousness.
WHO international drug-monitoring program. Adopted in 1968 as a pilot in ten countries with established ADR-reporting systems, the program has expanded considerably. National pharmacovigilance centers have been set up in many countries — 86 countries participate today, coordinated by WHO. The WHO Collaborating Centre analyses reports in the VigiBase database to: • identify early warning signals of serious ADRs; • assess risks; • study drug-action mechanisms and develop safer and more effective drugs. WHO plays an important role in providing expert opinions on all safety-related matters. The success of the WHO program depends entirely on the contributions of national centers. Ideally every country should have a pharmacovigilance center.
Conclusion. Despite its 40+-year history, pharmacovigilance remains a dynamic clinical and scientific discipline. It plays a vital role in handling the challenges posed by the constantly expanding drug range, which carries inevitable and sometimes unpredictable potential for harm. Every drug involves a trade-off between benefit and potential harm. That harm can be minimized through rational use of high-quality, safe and effective drugs, with good patient-physician compliance. Achieving this will: • improve public health and strengthen patient trust in the drugs used — boosting trust in healthcare as a whole; • limit drug-related risks; • provide regulators with the information needed to update drug-use recommendations; • bring up-to-date efficacy and safety information to practitioners.