A complex and vital relationship exists between a wide range of partners in the practice of drug safety monitoring. Sustained collaboration and commitment are vital if the future challenges in pharmacovigilance are to be met and the discipline is to continue to develop and flourish. These partners must jointly anticipate, understand and respond to the continually increasing demands and expectations of the public, health administrators, policy officials, politicians and health professionals. There is little prospect of this happening in the absence of sound and comprehensive systems that makes such collaboration possible. The partners concerned, and the present constraints under which they function, are described in this chapter. The constraints include training, resources, political support, and most especially scientific infrastructure. Understanding and tackling these would set the scene for future development of the science and practice of pharmacovigilance.
The WHO Quality Assurance and Safety: Medicines Team
The Quality Assurance and Safety: Medicines team is responsible for providing guidance and support to countries on drug safety matters. The team is part of the Department of Essential Drugs and Medicines Policy, within the WHO Health Technology and Pharmaceuticals cluster. The purpose of the department is:
to help save lives and improve health by closing the huge gap between the potential that essential drugs have to offer and the reality that for millions of people - particularly the poor and disadvantaged - medicines are unavailable, unaffordable, unsafe or improperly used.(6)
WHO works towards fulfilling this mission by providing global guidance on essential drugs and medicines, and working with countries to implement national drug policies. These are designed to ensure:
• equity of access to essential drugs
• drug quality and safety
• rational use of drugs.
The explicit objectives of the Quality Assurance and Safety: Medicines team are:
• to ensure the quality, safety and efficacy of all medicines by strengthening and putting into practice regulatory and quality assurance standards.
For this policy to meets its objectives, the scope of pharmacovigilance needs to be extended to include the safety of all related health technologies, including medicines, vaccines, blood products, biotechnology, herbal medicines and traditional medicines.
the Uppsala Monitoring Centre
The principal function of the Uppsala Monitoring Centre is to manage the international database of ADR reports received from National Centres.(7) In 2002 this database held nearly three million case reports. The majority of national contributing centres have easy electronic access to these. the UMC has established standardized reporting by all National Centres and has facilitated communication between countries to promote rapid identification of signals.
A sophisticated Bayesian confidence propagation neural network (BCPNN) programme was created in 1998, which partly automates the signal detection system, and provides earlier alert signals than previous methods.(8)
The effectiveness of this system depends on:
• the size of the database
• the quality of the reports received from the contributing centres
• the timeliness of such reporting
• an active and reliable reporting culture within participating countries.
An international advisory panel of clinical experts determines the validity and clinical importance of the signals generated.
In recent years the UMC has expanded its role as a communications and training centre and clearing-house for information on drug safety. Through
• mail discussion groups,
• website development,
• annual National Centre meetings,
the UMC team, in collaboration with the WHO, facilitates and encourages the international collaboration, which was identified in 1972 as being vital for the success of pharmacovigilance.
The terminologies developed within the WHO programme for coding adverse reactions and medicines have been widely adopted by National Centres, manufacturers and drug regulators. In recent years, the introduction of a new terminology known as MedDRA (Medical Dictionary for Drug Regulatory Activities) has replaced the World Health Organization Adverse Reaction Terminology (WHO-ART) in developed countries. WHO-ART remains the mainstay of communicating adverse reactions in most developing countries within the International Programme.
Another project at the UMC is the creation of an ADR monitoring system for herbal and traditional medicines. (The growing importance of such a system is further referred to in Chapter 4 on Drug Regulation (page 21-22)).
While the UMC has achieved much in improving the activities, support and recognition of individual National Centres, much more could still be done in providing training and encouraging expertise at a national level. There needs to be better consultation and communication between developed and developing countries when discussions on international harmonization of pharmacovigilance issues are taking place.
More effective communication of information is being promoted and encouraged through the WHO International Drug Monitoring Programme and the UMC. They are working towards playing a more pro-active role in working together with countries in addressing specific safety concerns and establishing a system that would make possible an evaluation of safety concerns of international importance by a supranational body of experts. An example of such a system, as it applies to vaccine safety, is described in Chapter 6 (page 30, footnote).
The National Pharmacovigilance Centres
At present, post-marketing surveillance of medicines is mainly co-ordinated by national pharmacovigilance centres. In collaboration with the UMC the National Centres have achieved a great deal in:
• collecting and analysing case reports of ADRs
• distinguishing signals from background ‘noise’
• making regulatory decisions based on strengthened signals
• alerting prescribers, manufacturers and the public to new risks of adverse reactions.
The number of National Centres participating in the WHO International Drug Monitoring Programme has increased from 10 in 1968 when the Programme started to 67 in 2002. The centres vary considerably in size, resources, support structure, and scope of activities. Collecting spontaneous reports of suspected ADRs remains their core activity.
National Centres have played a significant role in increasing public awareness of drug safety. As a result, pharmacovigilance is increasingly seen as more than a regulatory activity, having also a major part to play in clinical practice and the development of public health policy. This development is partly attributable to the fact that many national and regional centres are housed within hospitals, medical schools or poison and drug information centres, rather than within the confines of a drug regulatory authority.
The scope of activities of National Centres has expanded to include communication of information about benefit, harm, effectiveness and risk to practitioners, patients and the public. Major centres in developed countries have established active surveillance programmes using record linkage and prescription event monitoring systems (PEM) to collect epidemiological information on adverse reactions to specific drugs. Such systems have already been implemented in New Zealand, the United Kingdom, Sweden and the United States of America.(9)
In the nature of their work, National Centres have also become familiar with real or contrived drug scare crises, which they have managed with variable success. Some centres are also involved in training undergraduate and qualified healthcare professionals in pharmacovigilance and the importance of reporting ADRs. The extent of such activities varies between countries.
The source and extent of funding of different National Centres also varies significantly. Most ministries of health fund their National Centre, at least in part. The entire cost of a pharmacovigilance system, compared with the national expenditure on medicines or the cost of ADRs to the nation is very small indeed.(10)
With the rapid spread of drug information across the globe, there is a recognized need for routine and rapid communication between National Centres and between national regulatory authorities. Many regulatory authorities in different regions of the world have developed close ties with each other to discuss safety data obtained on particular medicines and on the regulatory decisions being made in response to them.
Policies and regulatory guidelines are often discussed between National Centres. The International Conference for Drug Regulatory Authorities (ICDRA), the Annual Meetings of National Pharmacovigilance Centres Participating in the WHO Programme for International Drug Monitoring and other similar conferences facilitate such discussions.
The development of pharmacoepidemiology as a discipline would not have happened without the collaborative efforts of the pharmaceutical industry and academia. The infrastructure of databases, registries and published studies to support post-approval surveillance activities can largely be attributed to the needs of the pharmaceutical industry and drug authorities. Borrowed from the financial sector, the concepts of risk assessment and risk management were modified to reflect the needs of healthcare.
The pharmaceutical industry has prime responsibility for the safety of medicines. Manufacturers are uniquely placed for monitoring the safety of medicines, from the start of drug development and thereafter throughout the lifetime of the drug. Many companies have developed innovative and efficient monitoring systems that have contributed to the detection of new safety signals. The pharmaceutical industry has made many technological advances in drug developments that have improved the safety of new drugs.(11)
The number of staff in the pharmaceutical industry involved in pharmacovigilance is growing. This has been in response to the high regulatory standards that have been set at national and international levels and the increasing requirement for post-approval monitoring set by national drug regulatory authorities. Communication and exchange of information between the industry and regulatory authorities has improved as a result of the regional and international harmonization arrangements that have emerged in recent years. Continuing professional education, patient education, and sponsorship by industry of drug information activities have also contributed to safer use of medicines.
Hospitals and Academia
The efforts of clinical pharmacology and pharmacy departments around the world have resulted in the development of pharmacovigilance as a clinical discipline, A number of medical institutions have developed adverse reaction and medication error surveillance systems in their clinics, wards and emergency rooms. Case-control studies and other pharmacoepidemiological methods have increasingly been used to estimate the harm associated with medicines once they have been marketed.
The expansion of scientific knowledge in drug safety is attributable to greater awareness and academic interest in this field. Academic centres of pharmacology and pharmacy have played an important role through teaching, training, research, policy development, clinical research, ethics committees (institutional review boards) and the clinical services they provide.(12) In many medical institutions, particularly in the developed world, ADR monitoring is recognized as an essential quality assurance activity.
Greater integration of pharmacovigilance into clinical practice is still needed. Drug safety should feature in the medical and pharmacy curricula. Access to updated, unbiased and clinically relevant drug information is currently inadequate. Research and postgraduate training in the field remains neglected by many schools of health sciences. The growing alliance between the industry and academia and drug regulatory authorities has implications for pharmacovigilance. These are referred to in Chapters 4 and 5.
The success or failure of any spontaneous reporting system depends on the active participation of reporters. Although limited schemes for reporting by patients have been initiated recently, health professionals have been the major providers of case reports of suspected ADRs throughout the history of pharmacovigilance.
Originally physicians were the only professionals invited to report as judging whether disease or medicine causes a certain symptom by exercising the skill of differential diagnosis. It was argued that accepting ADR reports from physicians only, would ensure high quality information and minimize the reporting of unrelated, random associations. Studies have shown, however, that different categories of health professionals will observe different kinds of drug related problems.(13, 14)
Only by inviting reports from all professionals involved in the care of patients will it be possible to detect the full spectrum of complications related to pharmaceutical treatment. If, for example, only general practitioners contribute to the pool of information, medicines used primarily by specialists will not be covered. To get a representative picture of the reality, all sectors of the healthcare system would need to be involved, such as public and private hospitals, general practitioners, nursing homes, retail dispensaries, and clinics for traditional medicine. Wherever medicines are being used there should be a readiness to observe and report unwanted and unexpected medical events.
Only a patient knows the actual benefit and harm of a medicine taken. Observations and reports made by a health professional will be an interpretation of a description originally provided by the patient, together with objective measurements. Some believe strongly that direct patient participation in the reporting of drug related problems will increase the efficiency of the pharmacovigilance system and compensate for some of the shortcomings of systems based on reports from health professionals only.(15)
Patients who suspect they have been affected by an ADR are normally recommended to report to their doctor to enable the doctor to report it to the pharmacovigilance centre. However, since only 5% of doctors are estimated to participate in any pharmacovigilance system, this process is not efficient in ensuring that the patient's concerns are being recorded. There are studies indicating that systems for recording patient concerns might identify new drug safety signals earlier than the professional reporting systems alone.(16)
The contribution of other partners in drug safety including the media, advocacy groups, and lawyers needs to be acknowledged. These partners in pharmacovigilance have directly or indirectly facilitated the development of new and robust drug policies and decisions, while highlighting deficiencies and weaknesses in existing drug safety policies. In many instances these groups or individuals have the capacity to voice, and often change, public opinion. Moreover, they often facilitate active public debate and discussion of issues, which have direct relevance to their health. In many countries, policy-makers engage pro-actively with these partners when important matters of public interest are being considered. Co-operation and open lines of communication with non-governmental agencies including the media and consumer advocacy groups is likely to facilitate the creation of policies and legislation on pharmacovigilance which will enjoy widespread public support and confidence.
Much needs to be done to improve the relationship between these and other partners in pharmacovigilance. Misrepresentation of data and sensationalism of drug safety concerns in the media and in courtrooms has given rise to unfounded rumours and misplaced concerns about the safety of potentially valuable medicines.
Situations where there has been divergence in perspective on specific issues of safety between these and other partners, have resulted in a devastating impact on public confidence in regulatory bodies and other organizations. It is important that all partners recognize the considerable responsibility inherent in conducting activities relating to pharmacovigilance and of communicating them effectively.