Pharmacovigilance is an activity that has international significance. The current global network of pharmacovigilance centres, co-ordinated by the Uppsala Monitoring Centre, would be strengthened by an independent system of review. This would consider contentious and important drug safety issues that have the potential to affect public health adversely beyond national boundaries.
The Erice Declaration provides a framework of values and practice for collection, analysis and subsequent communication of drug safety issues. In providing for this, it asserts scientific and clinical issues on the one hand and the right of the public to be openly and fully informed on the other. It is a process that requires the active commitment of all involved - regulators, policy makers, health personnel, journalists, and (not least) pharmaceutical manufacturers. Scrupulous attention is required in the practice of pharmacovigilance to the issues of patient confidentiality.
Until recently, pharmacovigilance has been confined mainly to detection of adverse drug events that were previously either unknown or poorly understood. Its particular purpose was to contribute to a scientific understanding of the safety profile of a rather small number of drugs and to advise national regulatory authorities. In this document it is proposed that pharmacovigilance has the potential to move beyond its previously rather confined limits, and to serve a higher priority within public health. How that might happen is the subject of this chapter.
The burden of ADRs on public health
Despite the progress in pharmacovigilance that has been made, the burden on public health of ADRs remains significant.(60) Pharmacoeconomic studies on the costs of adverse reactions suggest that governments pay considerable amounts from health budgets towards covering costs associated with them.(70) In most countries the extent of this expenditure has not been measured.
The relationship between drug utilization patterns and the frequency of ADRs is poorly understood. However, it has become increasingly clear that the safety profile of medicines is directly linked with socio-political, economic and cultural factors that in turn affect access to medicines, their utilization patterns and public perceptions of them.(71, 72)
Drug utilization patterns are a major determinant in drug safety. For instance, the use of injectable medicines is more common in developing countries.(73) The parenteral route is likely to be associated with a high risk of adverse effects when injections are administered by inadequately sterilized equipment or poorly trained personnel. It is estimated that unsafe injection practice may lead to 780,000 to 1.56 million cases of hepatitis B, 250,000 to 500,000 cases of hepatitis C and 50,000 to 100,000 cases of HIV, annually in Africa.(74)
Self-medication and the lack of regulatory control measures over the sale of drugs further increase the risk of adverse reactions. The number of drugs in each prescription is highest in developing countries.(73) Factors such as illiteracy, concomitant use of traditional medicines, and the continued availability of impure and irrational pharmaceutical preparations contribute further to the risk.
Sound drug legislation, policy and an essential drugs programme that includes education of health professionals and patients in rational use of medicines are measures that should ensure better health care in all countries. Pharmacovigilance programmes could learn from the social mobilization practices that have been introduced in programmes for injection safety during immunization.(74) Social mobilization includes the three-pronged approach of:
• increasing public awareness,
• ensuring advocacy for decision-makers, and
• sensitization of health workers.
This encourages a consumer-based demand for safe medicines from a public that is informed about the safety profile of the medicines they use. The incorporation of pharmacovigilance into these activities should ensure that such measures are relevant locally, and that they promote public confidence in the process.
A partnership with patients
The ready availability of safer and more effective medicines of good quality inspires confidence and trust among patients. Pharmacovigilance is an essential part of the public programmes that underpin the reliable availability of sound medicines and it needs to be understood, supported and promoted at the highest levels.
For this to be achieved it is necessary for information about drug safety programmes to be easily available to the public so that the central role of the patient in the rational and safe use of medicines is understood. The public has in recent years increasingly influenced health professionals’ prescribing and patterns of drug use. This influence and greater awareness on the part of the public is attributable in part to the role of the media and Internet. High expectations of all service providers and medical institutions have developed.
Available information is not always reliable or scientifically valid. Direct advertizing to the consumer of prescription medicines has become commonplace in many countries. With this information patients feel more able to make their own therapeutic decisions, without assistance from doctor or pharmacist. The result has been increasing self-medication, licit and illicit sale of medicines over the Internet, and over-prescribing by doctors on patients’ demand. This has had considerable effect on increased prescribing.(75, 76)
If variations in the way medicines are used alter their safety profile, then there is a need for research to be conducted into how the process works. It also needs to be determined how access to drug information might influence patient safety, including patients’ perception of safety and the level of harm they are prepared to accept for different medicines. The social and cultural aspects of pharmaceutical use and the expectations and concerns of patients need to be further studied. The outcome of such research should make possible a better formulation of policies with a view to reducing patient risk.(77)
Public health programmes and responsible media coverage aimed at increasing access to drug information have made it possible for patients in many countries to take greater responsibility for their own health and for the decisions they make, and in the wider involvement of patients in decisions. This is reflected, in the creation of patient charters and patients’ bills of rights,(75) and in the work of patient advocacy groups. For example, patients with HIV/AIDS have been instrumental in creating international awareness of the impact of the disease and in improving access to therapies and communication of the associated risks. It is a welcome development in some places that patients’ concerns are now recognized as having a legitimate part to play at the heart of the decision-making process.
Such public health programmes, however, need not focus only on patients but could be used for the benefit of the general public as well. Such awareness-building and educational initiatives should also include children and elderly populations and could be greatly facilitated through partnerships with the media, educational institutions, other governmental and non-governmental organizations.
The Erice Declaration
The Erice Declaration (1997) represented significant progress in the light of these changes.(5) The Declaration challenges all the players:
• public health administration
• health professionals
• the pharmaceutical industry
• drug regulators
• the media
to strive towards the highest ethical, professional and scientific standards in protecting and promoting safe use of medicines. The Declaration urges governments and others involved in determining policies relating to the benefit, harm, effectiveness and risk of medicines to account for what they communicate to the public and patients. It calls for honesty when communicating drug safety information, even when such information may be incomplete and investigations still underway. It further asks that patients be openly informed of the facts, assumptions and uncertainties of the safety profiles of the medicines they use.
Some efforts have been made subsequently to achieve the goals formulated at Erice. Many regulatory agencies have websites to keep the public informed of their regulatory decisions and of drug safety concerns. In the Philippines and Australia videos and television programmes on ADRs are used to encourage reporting. Newsletters, bulletins and electronic distribution lists are increasingly used to communicate safety information globally. The WHO has made considerable efforts to train drug regulators and national immunization staff in communicating information to the media on adverse effects following immunization.c
c Details on the training in vaccines safety can be viewed at the following website: http://www.who.int/vaccines-access/Vaccines/VaccineQuality/GTN/aefi.htm
There are, however, several challenges facing pharmacovigilance programmes in achieving the aspirations of the Erice Declaration. These include the following:
(i) The difficulties and risks in communicating conflicting or contentious messages to the public. For instance, during the course of immunization programmes, communication of new safety concerns associated with the vaccine(s), or with programmatic errors, may result in a dramatic fall in coverage. Nonetheless, an approach of secrecy in such circumstances is likely to erode public trust and confidence, and it fails to respect the rights of the public to participate in decision-making. Not only do facts and figures need to be shared with the public, but also the process by which the data is assessed and how decisions are made should be shared openly.
(ii) Communication between national drug regulatory authorities and national pharmacovigilance centres needs to be improved so that regulatory decisions with possible international implications are rapidly communicated to regulators, to avoid widespread public concern or panic.
The pharmaceutical industry shares responsibility for sound communication with the public and health professionals for drug safety issues. This would be helped if manufacturers were routinely to communicate new safety information to regulators and pharmacovigilance centres in all countries where the drug concerned is marketed.
Regulators and manufacturers should have mutually agreed procedures for managing a crisis and for dealing with any new safety information. Manufacturer and regulator need to have an established common view and be in agreement as to what they regard as a new safety concern and what constitutes a crisis, so that problems of miscommunication and lack of trust are minimized when crises do arise.
A critical link in the chain of drug safety crisis management is the knowledge, competence and approach of journalists. They depend, for balanced reporting, on an understanding of how drugs work, of benefit, harm, effectiveness and risk, and on being able to distinguish between relative and absolute risk. That requires astute and thoughtful briefing from the responsible reporting official in the ministry of health or drug regulatory authority, and ability and understanding on the part of health reporters. A platform that encourages debate and discussion between regulators, manufacturers, consumers and the media would do much towards achieving these objectives. This applies as much to investigations in progress as it does to the conclusions that are reached.
The real cost, time, skills and human resources necessary to communicate drug safety issues pro-actively to the media, the public and health professionals need to be carefully considered. Such planning and resources need to be given a higher priority than in the past. Local issues such as culture, literacy and the socio-economic status of the population at risk may have bearing on the way the message is presented. Communication of information must ensure that participants’ rights to confidentiality are protected.
The costs to society of drug-related problems
When considering the cost of disease to society, ADRs and what is spent on detecting, preventing and managing them need to be included in the analysis. As pharmaceuticals become an increasingly prominent item in health budgets, and reliance is increasingly placed on physicians for controlling costs and curtailing their prescribing practices, pharmacovigilance has growing importance in addressing health costs. The management of HIV/AIDS in developing countries is illustrative of these issues. Within the debate over drug prices and intellectual property rights there are in addition important concerns regarding widespread use of potentially toxic medicines in developing countries with poor resources. Antiretroviral treatment regimens commonly involve two or three potentially toxic agents. Monitoring safety and efficacy in this situation involves regular laboratory testing of liver function, haematology, viral resistance by CD4 cell count and viral load. Furthermore, treatment of the serious and not uncommon adverse effects of such treatment, which include dermatological, hepatic, haematological, metabolic and neurological disturbances, adds even further to the health budget.
Pharmacovigilance activities are expanding around the world. This is reflected in the increasing number of national pharmacovigilance centres that have been established in recent years. There are still many countries where no formal systems for pharmacovigilance are in place. To ensure that the existing centres are effective, their impact on public health and health costs should be measurable and the benefits demonstrable. Only then will widespread support and long-term sustainability of pharmacovigilance centres be assured.
Encouraging product stewardship
Product stewardship may be defined as:
• the demonstrable process by which a business can identify and manage its safety, health and environmental performance as applied to the development, manufacture, marketing, use and disposal of its products (including packaging).d
d Modified from: Gibson B, Product Stewardship in the Chemical Industry. ATSE Focus 1997 (98): http://www.atse.org.au/publications/focus/focus-gibson.htm.
The principle requires pharmaceutical manufacturers to assume responsibility for the impact of their activities ‘from cradle to grave’, including consideration of the key influences in regulatory, customer and community contexts. The main underlying concern of the manufacturers is product liability, driven by legislation that requires products to have a safety profile which meets statutory requirements and public expectations. It is aimed at encouraging manufacturers to aspire to a new level of responsibility for the integrity of their products.
Responsibility for their products extends to all manufacturers (including those who produce generic medicines) and suppliers of raw materials. More broadly, the idea of stewardship is applicable to all industries. The principles of stewardship in the pharmaceutical industry include:
• compliance with policies and legislation that would assure patients’ and public confidence in their medicines
• research that is scientifically sound, ethical and safe for trial participants
• determining the impact of the manufacturing process on the safety of a medicine, for the patient and the environment (this includes adhering to principles of conservation and protection of the environment, and to recycling of resources)
• training and education of personnel and of patients in the optimum use of pharmaceutical products
• storage and transport of medicinal products in a way that ensures quality at the time they are used by patients
• safe disposal of waste, raw materials, and of the end-products and their packaging (for example, injections, chemotherapeutic agents)
• rational and appropriate use of medicines by patients and by health professionals, requiring sound drug information, good product information (package insert/data sheet), including information on benefit, harm, effectiveness and risk, and how the total package of information can be communicated most effectively
• ensuring that sales and marketing observe the highest ethical standards that will instil public trust and confidence.
Adoption of the idea of stewardship would have important implications for the activities of pharmaceutical manufacturers. Many have already partly adopted the principles, but much remains to be done before the industry can be said to subscribe to these standards and comply fully with them. The standards cannot be achieved by industry alone. Sound legislation, a competent national drug regulatory authority, and informed prescribers and consumers are necessary for stewardship to succeed.
Protecting patient confidentiality
When patients are prescribed medicines for prevention or cure of disease they have a right, of which they should be informed, to decide whether or not to accept what is offered. They are also entitled to confidentiality. Physicians have a duty to protect that right and to use information from treatment only in relation to that patient’s care, unless they are expressly allowed otherwise by prior informed consent.
These rights and duties are not absolute. In some instances, the needs of public health may override those of the individual patient for protection of confidentiality. Public health requirements such as mandatory notification of certain diseases may justify disclosure of patient information. But even when such disclosure is required in terms of public health need, it remains the responsibility of the health worker to protect patient confidentiality as far as possible.
In most countries, the law does not require that ADRs should be reported, and National Centres in those circumstances do not have the legal protection afforded where there are mandatory reporting systems. It is essential that healthcare personnel should obtain the consent of the patient when identity is disclosed on an ADR form or in a drug surveillance study.
It is ultimately in the patient’s interest that healthcare personnel should have access to good information from other patients who have been exposed to the drug. Only by encouraging reporting can regulatory agencies and manufacturers take responsibility for the safety, efficacy and quality of the drugs they have approved or marketed for public consumption.
National Centres have to maintain high standards of data protection when information has been received on patients who have not given their informed consent. Patients should also be helped to understand that the information they provide is likely to contribute to an international understanding of drug safety.(78)
International response to drug safety issues
Certain safety issues are likely to have a global impact with possibly serious consequences for public health. When this happens, a cohesive international assessment and response is needed.(79) Such a system would need to be supported by member countries. Its terms of reference should be quite clear and generally agreed. There would need to be access to all data relating to a product under consideration, including product information protected by secrecy laws and patient case records when necessary.
The aggressive marketing of new medicines by pharmaceutical manufacturers and the resultant rapid exposure over a short period of time of large numbers of patients to them warrant the creation of a system for global assessment of drug safety concerns. The WHO has supported the creation of an independent advisory panel composed of a broad spectrum of medical disciplines including clinical pharmacologists, regulators, academics and epidemiologists. The functions of this panel will be to provide advice to WHO on safety issues relating to medicinal products, including its Collaborating Centre for International Drug Monitoring (the UMC) and through it to the Member States of WHO.