PHARMACOVIGILANCE AN OVERVIEW
EFFECTIVENESS AND RISK ASSESSMENT OF THERAPIES
Ø Effectiveness and risk: benefit and harm
Ø Decision-making in risk situations
Ø Good decision-making practices
Effectiveness and risk: benefit and harm
“Estimating the risk and benefit of medicines among the populations exposed to them is essential to promote their rational and safe use and will enhance the tolerability and acceptability of mass-treatment programmes.”
The effectiveness and risk profiles of many of the medicines used in PHPs in the past have been established by long experience rather than on the basis of epidemiological evidence. The modern approach to public health requires that advice be given on the best general ways of approaching the management of diseases, notwithstanding the necessity for considerable freedom to modify therapy according to individual needs9.Because of the need for comparative effectiveness and risk profiles of treatment options to find the most useful medicine at the most reasonable cost, it is necessary to use the correct conceptual and practical approach to assessing the effectiveness and risk of medicines.
When new medicines are marketed, only data on animal pharmacology and toxicology, and limited information on their use in humans are available. The number of subjects who have received the medicine in randomized clinical trials before it is marketed may be as few as 100 and is never more than 5000. Although such trials are an irreplaceable tool for determining the potential benefits of the medicine, they provide only limited insight into the likely responses of patients in whom other medicines are administered concurrently; the effects on diseases other than the target disease; the effects of dose variation; nutrition, and many other factors. In clinical trials, only risks of greater than 1/1000, at best, are likely to be noted. At this stage it is not possible to say that degrees of efficacy and hazard have been established, i.e. the potential for effectiveness and risk. A practical level of knowledge of effectiveness and risk can be achieved only when tens of thousands of unselected patients have been treated, and information on the results has been gathered.
It is also important not to confuse benefit with effectiveness. Benefit, described as an overall good, is difficult to define for a society.
It is common to compare pre-marketing efficacy with the spontaneous reports of harm collected. Because the processes for collecting the information are totally different, great care must be taken in interpreting the results; indeed many assumptions need to be made before any interpretation is possible. Another common problem is the comparison of the efficacy and harm of a new medicine with what is much closer to a set of effectiveness and risk data for an older medicine, derived over years of experience.
Decision-making in risk situations:
In critical public health situations, decisions are made either by the PHP or by the national regulator on the basis of available evidence, informed by prior experience, political context and professional judgement.
The decision could be any of the following:
Ø Stop the programme; investigate effectiveness/risk.
Ø Continue the programme, but investigate effectiveness/risk.
Ø Undertake additional studies.
Ø Issue information of public interest.
Ø Issue new guidelines for the PHPs.
A concept central to decision-making is “acceptable risk”. The fundamental question is, “Acceptable to whom?” Individual patient health lies outside the scope of this document. These decisions are the responsibility of the health practitioner and are taken after discussion with his or her patient. The prescribing physician and the patient must still be at liberty to make their choice, although their decisions should be guided by the public health constraints specific to that locality, and based on reliable information.
Good decision-making practices:
The conventional decision-making process in public health needs to be strengthened to deal with quantitatively and qualitatively more complex issues arising out of new medicines being used in public health programme (PHPs).
Decision-making is the process of determining the actions to be taken, who should take them, and the order and methods of taking action. It also entails judgements on the best means of monitoring, follow-up and of communicating the appropriate information to the parties concerned. Decision making should follow three principles, namely:
Ø Transparency; and
Moreover, to achieve success, there is a need to consider each decision in terms of the following headings:
Ø Obtaining the best data and information
Ø The context of the decision
Ø De-nition of the steps to be taken to reach a decision, for example, by simplifying into sets of subsidiary decisions, and being able to sum the results of such smaller decisions into an overall strategy
Ø Communication and action
Ø Revision of the original decision as necessary.
Roles and responsibilities(9,13,15)
Where established, the national pharmacovigilance centre will be responsible for the development of pharmacovigilance in the public health system, will promote pharmacovigilance in the PHPs and sensitize professionals and public health staff to the reporting of adverse reactions and irrational use of medicines.
Role of pharmacist(10,17,19)
Ø Participate in spontaneous Reporting of Adverse Events.
Ø Also report (even if no adverse event).
Ø Medication errors.
Ø Exposure during pregnancy
Ø Monitor clinical status of patients.
Ø Identify the correct ADRs not side effects.
Ø Get more information.
Ø Investigate at hospital level.
Ø Help doctors to fill-up the forms.
Ø Keep patient’s record if more information needed.
Patients and the public
Public awareness about adverse reactions, early reporting and management are essential for ensuring patient confidence, in and adherence to, pharmacotherapy. In some countries patient reporting is accepted and can add value, but this needs to be separate from involvement of patient interest groups can be sought while formulating the programme and should be part of the feedback–communication link.
Primary health-care workers
It is the responsibility of the primary health-care provider to detect, investigate, manage and report ADRs. These staff will need training on the importance of adverse reactions, diagnosis, basic principles of causality assessment and the important elements of the adverse reactions reporting form.
Patient education is an important role of the primary health-care provider. Educating the public on ADRs is important for promoting adherence. Counselling and explanation about adverse reactions will promote patients’ confidence and adherence.
The reporting of adverse reactions needs continuous stimulation. It is important to achieve a positive attitude towards pharmacovigilance. To encourage reporting, the following steps should be of help:
Ø Easy access to reporting forms;
Ø Acknowledgement of receipt of a report and provision of feedback to the reporter;
Ø Participation of reporting staff in pharmacovigilance meetings, and of pharmacovigilance staff in professional meetings; and
Ø Collaboration with the national pharmacovigilance centre.
Other health-care workers
Health-care workers outside the government system should also report adverse reactions. These would include, among others, nongovernmental organizations and charitable health facilities.
District investigation team
The district investigation team plays a central role in monitoring adverse reactions. The team should comprise a clinician in the district hospital, head nurse, pharmacist and district health officer or programme manager. The team is responsible for following up adverse reactions reported from all the health facilities within their district.
(In the case of vertical programmes the specific programme manager will be responsible for medicines pertaining to that programme.) The team will play an important role in collaboration with and encouragement of reporting by primary health centre staff and hospital staff. Their detailed follow-up of suspected ADRs will be used to assess causality.
When dealing with reports of ADRs, the district investigation team should:
Ø Seriousness (including all deaths);
Ø Severity; exposure to medicine during pregnancy;
Ø Apparent signals of new reactions; and
Ø Patterns of suspected reactions which although not serious, may affect adherence and the success of the programme.
Refer all reports to the national pharmacovigilance coordinator for processing and review by the Expert Safety Review Panel (ESRP).
National pharmacovigilance coordinator
The coordinator, who should be on the staff of the national pharmacovigilance centre, should function as the focal point for the national pharmacovigilance system in the PHP.
Ideally this should be a full-time position. The responsibilities of the national coordinator would include coordination, communication, integration, training and supervision of the pharmacovigilance-related activities of the district investigation teams. This person would also serve as member or secretary of the national ESRP.
The coordinator should ensure that the ADR reports are processed appropriately for assessment by the ESRP. These would generally fall into one of three categories:
Ø Reports selected for investigation by the district investigation team, which should be considered in detail;
Ø Reports considered to be a signal of a new adverse reaction; and
Ø All other reports, which may be presented in summary format, so that an overall reaction profile of the medicine can be obtained.
National medicines regulatory authority
The regulatory authority will receive reports and recommendations from the ESRP. It will perform risk assessment and consider options for regulatory action which may involve requiring the manufacturers to make changes in the labelling of their product or may be a restriction in the use of the product, a temporary suspension or complete withdrawal. The regulatory authority may liaise with other national MRAs and it should always pass on the information on any action taken to WHO.
Pharmaceutical industry and marketing authorization holders
Pharmaceutical manufacturers are legally responsible for the safety and effectiveness of medicines while the product is available in the marketplace. They should provide medicines of good quality and have stewardship of their products. As essential players in the provision of medicines, they should be kept informed of the results of monitoring and relevant decisions. They also have a duty towards assessing the effectiveness and safety of a PHP and the benefits to patients. They should report adverse reactions both to the national pharmacovigilance centre (and in the absence of such to the MRA) or PHP and, in countries with no MRA they should also report to WHO through the disease control PHP.
It is important that the media are involved from the start of a PHP and that the need for the programme is publicized together with the need for pharmacovigilance. The pharmacovigilance programme should be explained and good lines of communication should be set up between the media and the ESRP or the designated liaison person, to ensure the availability of authoritative information. The need for good information should be anticipated so that potential crises can be dealt with quickly and effectively, and public confidence maintained.
When communicating with the media, the following information should be available:
Ø A complete account of any event of concern and its appropriate context (in terms that will be understood by the lay public), e.g. a clear statement that an event is an isolated occurrence, to prevent concern that it may be widespread.
Ø The likelihood that there will be new cases linked to therapy with the medicine.
Ø An outline of actions taken or planned (depending on the stage, this will range from a plan of action to a completed investigation).
Ø The cause of the event (when identified with reasonable certainty).
Ø The corrective action that has been or will be taken.
Ø Guidance to the public on how to respond to concerns over the medicine including contact information for reporting further adverse events.
It is useful to assess the impact of media communications on public awareness and attitudes as this will assist the development of future communication strategies.
The roles of WHO and the International Advisory Committee:
The role of WHO At an international level WHO will play a key role. While supporting countries to conduct PHPs, WHO and its regional offices have a responsibility to promote the establishment and building of sustainable safety monitoring systems. WHO will take a lead role in supporting Member States in the safe use of medicinal products. WHO will serve as a repository for information from both pharmacovigilance programmes and PHPs, and will disseminate this information appropriately.
WHO will identify areas requiring research and encourage and support initiatives to conduct operational research. It will assist countries to define and develop policy on monitoring the safe use of medicinal products and it will respond to controversial issues on the safety of medicines that threaten the use of medicines in a national or international PHP. It will promote and encourage uniformity of terminology and will promote and develop resource materials and provide leadership in training and capacity development.
Advisory Committee on Safety of Medicinal Products (ACSoMP)
An Advisory Committee has been established by WHO to advise on issues that:
Ø Are important to national or international programmes and have the potential to affect them adversely if not resolved;
Ø Cannot be met by structures and/or institutions and/or systems that are already available;
Ø Respond to identified needs of a country that may be beyond the capability of the country or countries themselves; such responses should be made within an appropriate period of time, taking into account any existing information and the urgency of the issue.
WHO Programme for International Drug Monitoring
National pharmacovigilance centres are functioning as an international network coordinated by the WHO Programme for International Drug Monitoring. The Programme has achieved much in improving the activities, support and recognition of individual national pharmacovigilance centres.
It plays a key role as a communication and training centre and clearing-house for information on the safety of medicines. The WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden manages the international database of adverse reaction reports received from national centres. In 2005 this database held over 3.5 million case reports. The majority of contributing national centres has ready electronic access to these. The Centre has established standardized reporting by all national centres and has facilitated communication between countries to promote the rapid identification of signals. The terminologies developed within the WHO programme for coding adverse reactions to medicines have been widely adopted by national centres, manufacturers and medicine regulators.
The WHO Collaborating Centre analyses the reports in the database to:
Ø Identify early warning signals of serious adverse reactions to medicines; evaluate the hazard;
Ø Undertake research into the mechanisms of action to aid the development of safer and more effective medicines.
Through an advisory committee, WHO plays an important role in the provision of expert advice on all matters relating to the safety of medicines. The Committee also exists to facilitate consistent policies and action among member countries and to advise those who may be concerned about action taken in another country.
The success of WHO’s International Drug Monitoring:
It is entirely dependent on the contributions of national pharmacovigilance centres. Such centres provide an essential pool of experience and competence which has been instrumental in the continuous development of the WHO programme and of pharmacovigilance as a whole.
Despite its 40-year history, pharmacovigilance remains a dynamic clinical and scientific discipline. It continues to play a crucial role in meeting the challenges posed by the ever increasing range and potency of medicines, all of vitamins unpredictable potential for harm. When adverse effects and toxicity do appear especially when previously unknown it is essential that these are reported, analysed and their significance communicated effectively to an audience that has the knowledge to interpret the information. Which carry an inevitable and some-For all medicines there is a trade-off between the benefits and the potential for harm. The harm can be minimized by ensuring that medicines of good quality, safety and efficacy are used rationally, and that the expectations and concerns of the patient are taken into account when therapeutic decisions are made. To achieve this is to:
Ø Serve public health, and to foster a sense of trust among patients in the medicines they use that would extend to confidence in the health service in general;
Ø Ensure that risks in drug use are anticipated and managed;
Ø Provide regulators with the necessary information to amend the recommendations on the use of the medicines;
Ø Improve communication between the health professionals and the public;
Ø Educate health professionals to understand the effectiveness/risk of medicines that they prescribe. This is the important role of pharmacovigilance.
Experience has shown that for a country to be able to rely on its own pharmacovigilance programme a number of elements need to be in place. These are as follows:
Ø A dedicated pharmacovigilance centre, independently funded (usually by the state), and staffed by a person or persons with expert knowledge of drug safety and of the evaluation of reports of adverse events;
Ø Links, electronic and personal, between the pharmacovigilance centre and WHO, specifically with the Uppsala Monitoring Centre;
Ø Close operational ties with the national MRA that fullfil the mutual needs of the MRA and the pharmacovigilance centre for the evaluation and continuous monitoring of the safety of medicines;
Ø Access to comprehensive and unbiased drug information relevant to the medicines available in the country;
Ø To achieve the objective of integrating pharmacovigilance with public health systems the following are necessary. (What follows applies to countries with a minimum national pharmacovigilance system in place. Countries without such a national system will be covered later in this section.)
Ø The national pharmacovigilance programme should have clinical underpinning, and should be known to and be actively supported by the ministry of health, health professionals and the academic sector.
The programme should have ready access to sound and independent drug information (particularly information on drug safety) and it should serve as a robust and dependable reference centre. The public should know of its existence, and have trust in the judgement and expertise of its professional staff. There should be adequate financial support from the state to enable the programme to perform these functions.
Ø The national pharmacovigilance centre may be based physically (but not necessarily so) at the ministry of health, within the national MRA, within a leading state hospital, or at an academic school of pharmacy, medicine or health sciences. Whatever arrangement is made, there should be close collaboration, exchange of information, and mutual technical support between the centre and the MRA.
Ø A national medicines safety review committee (ESRP) for adverse reactions that advises both the MRA and the national pharmacovigilance centre, and that has strong clinical representation in its membership, should provide support and focus for the work of the national centre, and for the MRA.
Ø Finally, there should be regular opportunities for the professional staff of pharmacovigilance centres to upgrade their knowledge and experience through training, study and research
Ø Ideally in conjunction with colleagues in public health.
The following is a summary of some of the serious challenges facing pharmacovigilance programmes in the next ten years, describing in brief the potential implications of such trends on the evolution of the science.
Major challenges are:(6,20,23,24)
Ø Web-based sales and information
Ø Broader safety concerns
Ø Public health versus pharmaceutical industry economic growth
Ø Developing and emerging countries
Ø Attitudes and perceptions to benefit and harm
Ø Detection of ADRs
Ø Assessment of ADRs
Conduct on-going research to assess the cost-effectiveness of contemporary pharmacovigilance systems in contributing to patient welfare and public health. Consider the sensitivity and specificity of current signal detection and assessment methods and the extent to which contemporary pharmacovigilance systems have been successful in detecting and preventing potential disasters while avoiding the premature withdrawal of safe and useful medicines from the market.
Taking medicines, and prescribing them, are among the commonest of activities of people who are unwell and of those who care for them. It makes sense that those medicines should be monitored to equally demanding standards as those evident in the development and evaluation of drugs, and that prescribing habits and the extent of rational and cost- effective use should be reviewed.
Responsibility for the holistic approach to drug safety that is encompassed in the science and practice of pharmacovigilance, as reflected in this report, has to be shared if ideal practice is to be achieved. The scientists, clinicians, pharmaceutical manufacturers, drug developers, regulators, public policy makers, patients and the general public all have their own complementary roles in achieving what is envisaged. Among the important issues are information, information sharing and broader communication. What we need is a continuing and dynamic development of modern professional practice. We must recognize that solutions to the challenges will come from those inspired and committed individuals and institutions round the world with a vision of improved public health and patient safety. Most important in this venture, is the need for a new spirit of sharing of information and intelligence in line with the vision and aspirations of the Erice Declaration.
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