Pharmacovigilance an essential tool
Safety monitoring of medicinal products is a series being prepared to provide
up-to-date information on various aspects of pharmacovigilance

This volume presents a critical examination of the strengths and weaknesses of present systems of safety monitoring in order to increase their impact and provides an overview of the challenges facingpharmacovigilance in the future. It also highlights the importance of collaboration and communication at local,regional and international levels, to ensure pharmacovigilance delivers its full benefits.
ISBN 92 4 159015 7
Pharmacovigilance an essential tool
WHO Library Cataloguing-in-Publication Data
The safety of medicines in public health programmes: pharmacovigilance an essential tool.
1. Adverse drug reaction reporting systems.
2. Drug monitoring.
3. Product surveillance, Postmarketing.
4. National health programmes.
I. World Health Organization.
ISBN 92 4 159391 1 (NLM classification: QV 771) World Health Organization 2006
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Pharmacovigilance an essential tool
Chapter 1 Introduction
Chapter 2 Public health programmes using medicines
2.2 The public health environment 2.3 Public health programmes for disease control 2.4 Future needs of public health programmes Chapter 3 Pharmacovigilance
3.1 Origins of pharmacovigilance 3.3 The cost advantage 3.4 Current practice 3.5 Good pharmacovigilance practice Chapter 4 Effectiveness and risk assessment of
4.1 Effectiveness and risk: benefit and harm 4.2 Decision-making in risk situations 4.3 Good decision-making practices Chapter 5 Pharmacovigilance and public health
programmes: current situation
Chapter 6 Integration of pharmacovigilance into public
6.2 Justification 6.3 Requirements for pharmacovigilance in public health 6.4 Spontaneous reporting 6.5 Cohort event monitoring 6.6 Roles and responsibilities 6.7 Where there is no national pharmacovigilance system 6.8 Training and capacity building 6.9 Evaluation of the system 4 Contents
Chapter 7 Conclusions and recommendations
Summary table of roles and responsibilities
for pharmacovigilance in public health

World Health Assembly Resolutions
Contents 5
The Quality Assurance and Safety of Medicines team of the World Health Organization(WHO) aims to assure the safety of medicines by ensuring reliable and timely exchangeof information on drug safety issues, promoting pharmacovigilance activities throughoutthe Organization and encouraging participation in the WHO Programme for InternationalDrug Monitoring. This team is developing a series of publications on safety monitoringof medicinal products. This text on pharmacovigilance in public health programmes wasdeveloped in consultation with the WHO Collaborating Centre for International DrugMonitoring and the national pharmacovigilance centres participating in the WHOProgramme for International Drug Monitoring. The draft was widely circulated anddiscussed at two informal consultations with international experts in pharmacovigilanceand public health experts.
Sincere thanks for their contributions and critical review of the text are due to thefollowing persons: Dr Z. Ali Gorar, Ms N. Arthur, Dr A. Bentsi-Enchill, Dr D. Coulter,Dr M.R. Couper, Dr P. Duclos, Professor S.A. Edlavitch, Professor I.R. Edwards, Dr P. Folb, Dr S. Gressitt, Ms A. Haq, Dr K. Hartigan-Go, Dr N.A. Kshirsagar, Dr R. Laing, Dr V.K. Lepakhin, Ms Y. Maruyama, Dr B. Mintzes, Professor M. Montagne, Mr S. Olsson, Dr S. Pal, Dr L. Rägo, Dr J. Raine, Professor M. Reidenberg, Mr B. Rowsell, Ms C. Scudamore, Dr R. Soulaymani-Bencheikh, Dr Tagwireyi, Dr P. Trouiller, Dr E. Van Ganse and Dr X. Zhang.
Particular thanks are due to Dr D. Coulter, Dr N.A. Kshirsagar andDr R. Soulaymani-Bencheikh for their drafting of the original manuscript.
6 Preface
Pharmacovigilance is defined as "the science and activities relating to the detection,assessment, understanding and prevention of adverse effects or any other possible drug-related problems".
Pharmacovigilance is an arm of patient care. It aims at making the best use of medicinesfor the treatment or prevention of disease. No one wants to harm patients, butunfortunately any medicine will sometimes do just this. Good pharmacovigilance willidentify the risks and the risk factors in the shortest possible time so that harm can beavoided or minimized. When communicated effectively, this information allows for theintelligent, evidence-based use of medicines and has the potential for preventing manyadverse reactions. This will ultimately help each patient to receive optimum therapy, andon a population basis, will help to ensure the acceptance and effectiveness of publichealth programmes.
Significant harm to a few patients can destroy the credibility, adherence to and success ofa programme. Rumours and myths about the adverse effects of medicines can spreadrapidly and are difficult to refute in the absence of good data. Pharmacovigilance canprovide these data. It can also provide evidence of other types of medicine-relatedproblems including treatment failure, counterfeit medicines, poor quality medicines,interactions between medicine and food and the incorrect use of medicines. Goodpharmacovigilance practice can generate the evidence that will inspire public confidenceand trust.
Pharmacovigilance incorporates and provides training in the identification of adversereactions, data collection, processing and analysis. Importantly, these activities allow forthe identification of previously unsuspected adverse reactions as well as identification oftheir effects in pregnant women and in the very young or old, which, for new medicines,are generally unknown. The information collected also provides the tools for the effectivemanagement of problems. These include communication and minimization of risk.
In developed countries, the cost of adverse reactions in the general population is veryhigh and under-recognized. Against the background of the high disease burden andmalnutrition present in many underdeveloped countries, this cost could be proportionatelyhigher. In any public health programme, a well-integrated pharmacovigilance system mustultimately result in cost savings through early recognition and management of these risks.
Those countries that lack the necessary facilities, expertise and resources forpharmacovigilance arguably need them the most. In working to achieve this, it isimportant that the traditional division between safety of medicines on the one hand andpublic health on the other should cease to exist. The development of pharmacovigilancewithin a public health programme should be seen as an important opportunity for thedevelopment within the local health service of a comprehensive nationalpharmacovigilance system and should be seen as an obligatory investment in the futurepublic health of the territory.
Executive Summary 7
A strength of pharmacovigilance is its international nature. Under the stimulus andcoordination of the World Health Organization (WHO) and its Collaborating Centre forInternational Drug Monitoring (the Uppsala Monitoring Centre), there are currently 79national centres networking in a strong international programme. These national centrescollaborate in the WHO Programme for International Drug Monitoring, to collect reportsof suspected adverse drug reactions (ADRs) and after review, send them to the UppsalaMonitoring Centre for entry into the WHO database. This is the largest database of ADRreports in the world (over 3.5 million case reports) and is a prime resource for generatingsignals of previously unrecognized ADRs and for the study of questions on the safety ofmedicines. This database would have added value if it included reports about medicinesused in public health programmes and could also be a valuable resource for theprogrammes themselves.
The integration of pharmacovigilance may be crucial to the success of public healthprogrammes using medicines. This document demonstrates that pharmacovigilance canand should be an integral part of every public health programme that uses medicines inorder to optimize the use of scarce health resources and prevent potential tragedies. Toexplain how that might happen, and why, is the purpose of this report.
8 Executive Summary
The 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;— detect problems related to the use of medicines and communicate the findings in a — contribute to the assessment of benefit, harm, effectiveness and risk of medicines, leading to the prevention of harm and maximization of benefit; — encourage the safe, rational and more effective (including cost-effective) use of — promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public.
The purpose of this document is to present the case for integrating pharmacovigilance asan essential component of public health programmes (PHPs) that use medicines. It isimportant that active pharmacovigilance is undertaken by all PHPs that use medicinesbecause no medicine is without adverse consequences although these vary in severity andfrequency. This document highlights the importance of collaboration and communicationbetween pharmacovigilance systems and PHPs at both the national and internationallevels to ensure full integration. Where there is no established pharmacovigilance system,the document argues for the importance of using a PHP as an entry point for theestablishment of a fully functioning pharmacovigilance system that informs and advisesthe medicines regulatory authority. The document also highlights the critical strengthsand weaknesses of both pharmacovigilance systems and PHPs.
This document is intended primarily for policy-makers and programme managers. Moredetailed information on particular programmes should be collected and made available bythe specific PHP.
Objectives 9
The purpose of this document is to demonstrate that pharmacovigilance can andshould be an integral part of every PHP that uses medicines to optimize the use ofscarce health resources and prevent potential tragedies. The use of medicines is an important aspect of many PHPs that are designed to improvethe health of a target population. Their cost to the health budget is between 6% indeveloped countries and 45% in some developing countries, but there are huge variationsbetween both developed countries and developing countries. Medicines are important notonly because of their capacity to treat and prevent disease and to support PHPs, but alsobecause the confidence of the public in the health policies of their countries isinextricably linked to their confidence in the availability of medicines that are safe andeffective. All medicines carry some risk of harm and it is important to monitor theireffects, both intended and unwanted, so that good evidence is available upon which tobase an assessment of risk versus effectiveness or risk versus benefit. Furthermore,particularly with new medicines, the early identification of unexpected adverse reactionsand their risk factors is essential, so that the medicines can be used in an informedmanner with the least chance of harm. This is the role of pharmacovigilance. Informationgathered during pharmacovigilance may also assist in selecting the most appropriatemedicine for future use.
Despite the progress that has been made in pharmacovigilance, the burden on publichealth of adverse reactions to medicines (traditionally referred to as ADRs) remainssignificant. Pharmacoeconomic studies on the costs of ADRs suggest that governments pay considerable amounts from their health budgets towards covering the costs associatedwith them. In a meta-analysis of 39 prospective studies from hospitals in the UnitedStates, it was shown that ADRs ranked from the fourth to sixth leading cause of death (1).
Extrapolation of data, from a more recent prospective study in England to the wholeNational Health Service bed base, suggests that for patients aged > 16 years, at any onetime the equivalent of up to seven 800-bed hospitals may be occupied by patients admitted with ADRs (2). There are also costs associated with ADRs in primary healthcare, but these are more difficult to assess. To the direct costs should be added the indirect costs of adverse reactions, such as loss of productivity. There are now sufficientdata available to indicate that the provision of adequate strategies to detect and preventadverse reactions is a cost-effective commitment of resources.
Health requirements and the use of medicines in different countries vary considerably formany reasons, including different burdens of disease, economic, ethnic, cultural anddietary factors, and the level of development of a system for the regulation of medicines.
Decisions concerning the effectiveness and safety of a product need to be considered ineach country's specific context. Vigilance regarding both safety and effectiveness ofmedicines must become a priority area within public health.
WHO has produced guidelines for setting up a national pharmacovigilance centre (3) andmany WHO PHPs have developed their own guidelines. The vaccines example is includedin Annex 1. This document offers a critical examination of the strengths and weaknessesof both pharmacovigilance systems and public health systems. It describes the roles andresponsibilities of all parties involved and anticipates the developments that will benecessary to enable both pharmacovigilance and PHPs to meet the challenges of thecoming years. The increasing public expectation of safety is one of the major elements ofthe need for improving the safe use of medicinal products. As effective medicinesbecome more widely available, there is an increasing demand for their use by the publicand it is imperative that these medicines are monitored for safety. Nationalpharmacovigilance centres cannot address this issue alone. They need to work togetherwith other parties including the local regulatory authority, managers of PHPs, healthprofessionals, academia, governments, the pharmaceutical industry, patients andconsumers, and the media.
The important components of a PHP are education, environmental modifications,nutrition intervention, lifestyle and behavioural changes, preventive measures suchas immunization, screening for hypertension and breast cancer and, in addition,pharmacotherapy. 2.1 Introduction2.2 The public health environment2.3 Public health programmes for disease control2.4 Future needs of public health programmes Public health is defined as the organized efforts of society to protect, promote and restorepeople's health. It is the combination of science, skills and beliefs that is directed to themaintenance and improvement of the health of all the people through collective or socialactions. The programmes, services and institutions involved focus on the prevention ofdisease and the health needs of the population as a whole. Public health activities changein response to variations in technology and social values, but the goals remain the same:to promote health and to reduce the amount of disease, premature death and disease-related discomfort and disability in the population.
Health promotion strategies contribute to the improvement of health and the prevention ofdiseases in developing and developed countries alike. Public health strategy is determinedin each country according to the epidemiology of prevalent diseases and the localcircumstances.
Developing countries are facing a major challenge in tackling the communicable diseasesthat are responsible for high rates of morbidity and mortality. Infectious diseases forwhich effective treatment has existed for a long time, such as some diarrhoeal andrespiratory diseases in children, continue to take their toll. Communicable diseases suchas tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome(HIV/AIDS), sexually transmitted diseases (STDs), malaria, schistosomiasis, amoebiasis,leprosy, trachoma, lymphatic filariasis, intestinal helminthiasis, onchocerciasis,leishmaniasis and trypanosomiasis add to the disease burden. Noncommunicable diseasescaused by environmental pollution and chronic diseases that result from changinglifestyles, dietary habits and patterns of behaviour add to the problem. In these countries,access to medical care is poor, largely because of the low socioeconomic level of thepopulations, but also for cultural and logistical reasons such as poor transportationinfrastructure. Health authorities include in their basic health package PHPs aimed atreducing morbidity and mortality associated with the major common diseases. Theimportant components of a PHP are education, environmental modifications, nutritionintervention, lifestyle and behavioural changes, preventive measures such asimmunization, screening for hypertension and breast cancer and, in addition,pharmacotherapy.
12 Public Health Programmes Using Medicines
Many PHPs are based on the direct administration of medicines or vaccines for theprophylaxis, treatment and control of a disease. Interventions aimed at achieving theassigned goal (i.e. reduction of morbidity and mortality rates) include mobilization ofresources both nationally and internationally to support the different aspects of theprogramme, including the mass distribution of free medicines. These programmes may beinitiated by countries themselves, or under the leadership of international organizations,particularly WHO and the United Nations Children's Fund (UNICEF). They aim todecrease morbidity and/or mortality rates or even to totally eradicate specific diseases.
WHO supports Member States in initiating, organizing, guiding and implementing anumber of clinical programmes. The programmes are functional thanks to the keenness,interest and support of many donors and sponsors, such as WHO, UNICEF and privatesector organizations. The pharmaceutical industry is increasingly involved in eitherdonating, or providing at reduced cost, medicines for direct administration to largepopulations and communities through a number of public health or disease controlprogrammes.
Consumers and patients of affected communities are not usually involved directly in thedecision-making process of the PHP. However, they influence the success of the desiredoutcome by accepting or rejecting the programme. The success of PHPs depends on theactive participation of the population and on multisectoral involvement.
2.2 The public health environment
Without good guidance and training programmes for health-care workers indeveloping countries, patients could be at an increased risk of medication errorand/or preventable ADRs. 2.2.1 Disease2.2.2 Population2.2.3 Medicine Counterfeit medicinesSubstandard medicinesDonated medicinesMedicine interactionsIncorrect use of medicines 2.2.4 Health-care provider2.2.5 Health-care system In developing countries PHPs are conducted by agencies and health workers with a widevariety of skills and expertise. Patients do not usually have direct contact with a physicianas would be usual with PHPs in developed countries. Consequently, without goodguidance and training programmes for health-care workers, patients in developingcountries could be exposed to higher risks of medication error and/or preventable ADRs.
These risks could be related to disease, population characteristics, medicine, health-careproviders or the health-care system. The influence of these factors is discussed below.
The diseases managed by the PHPs are not always well-diagnosed clinically. Treatment isoften initiated in the absence of an adequate diagnosis and there may be insufficient Public Health Programmes Using Medicines 13
follow-up of patients. For example, because of inadequate diagnostic facilities, it iscommon clinical practice for patients to be given presumptive treatment for malariaalthough many of the patients treated will not have the disease (4).
Public health programmes may treat a large population over a short period. To meet thespecific needs of a particular programme, the community could be treated in one of threedifferent ways: i.e. en masse, case-contact or individual treatment. Under theseconditions, some of the patients treated may not have the disease, or treatment could begiven to patients in whom there are contraindications to the use of the medicine (e.g.
pregnant or breastfeeding women, young children or elderly people). In a study in Brazil,it was found that, of the medicines used during pregnancy, 40% were not from the"approved safety" category and 3% were clearly contraindicated (5).
In addition, factors such as literacy, nutrition and food habits in the community can haveimportant consequences for adherence, therapeutic effectiveness and drug safety. Forexample, patient information on the medicines used is often absent, inadequate or tootechnical and is seldom in the vernacular. This could affect patients' comprehension ofthe correct way to use the medicines. Some medicines can compound nutritionalproblems in patients suffering from pre-existing malnutrition (e.g. nutritional deficienciesdue to severe diarrhoea caused by antiretrovirals).
Huge quantities of medicines are used each year; for example, more than US$ 316 billionwas spent on medicines in 2000. However, patterns of consumption differ between high-and low-income countries. In high-income countries, "originator" (patented)pharmaceuticals account for two thirds of sales of all medicines. The total sale ofmedicines grew substantially between 1990 and 2000. In low-income countries suchpharmaceuticals account for only about one third of total sales.
Medicines can be generic with low commercial value (for example mebendazole), newmedicines with which there is limited clinical experience (e.g. new antiretrovirals) or stillbe undergoing clinical trials. Government agencies may be unable to exercise control overmedicines of doubtful quality.
In some cases, access to a medicinal product is not through qualified health workers butthrough alternative systems, for example, medication may be purchased from pharmaciesor street vendors.
Counterfeit medicines Another widespread problem is that some medicines are counterfeit (Fig. 1) (6).
Antibiotics and other essential medicines are often counterfeited and their use leads totreatment failure and sometimes death. In many cases counterfeit medicines are positivelydangerous and detrimental to public health in terms of the human suffering they causeand the increased burden on the health services. Patients who take counterfeit medicinesmay not respond to treatment as quickly as they should and, in some instances, they maynot respond at all. Treatment with ineffective counterfeit medicines such as antibioticsmay have a deleterious effect on large numbers of the population. In extreme cases, 14 Public Health Programmes Using Medicines
Figure 1. Reports of counterfeit medicines by therapeutic class received by WHO 1999–2002Source: WHO database. E. Wondemagegnehu, 2002. QSM/EDM counterfeit medicines may cause serious harm to health or exacerbate the conditionsbeing treated because of the harmful ingredients they contain. In one case, it is allegedthat placebo tablets containing no active ingredients were stolen and sold as acontraceptive medicine, leading, it was claimed, to unexpected pregnancy (7).
Substandard medicines In some countries an average 10–20% of medicines fail laboratory tests for quality(unpublished data). Substandard products could result from poor manufacturing practices,unsuitable packaging, storage and distribution; or when generic drugs are produced byunregistered manufacturers. Fig. 2 shows the high failure rate in quality control tests forchloroquine tablets in some sub-Saharan African countries. This figure highlights theneed to test not only for potency (amount of active ingredient), but also for dissolutionrates of tablets and capsules to ensure availability of the active ingredient. Poor qualityantibiotic preparations may also contribute to the development of resistance to antibiotics.
There have been several tragic examples of the results of using substandard medicines inwhich diethylene glycol (DEG) has been incorporated in pharmaceutical preparations,fraudulently or by mistake, leading to the death of more than 500 people, mostlychildren. The United States Congress passed the Federal Food, Medicine & Cosmetic Actin 1938, in reaction to a public health accident that occurred in 1937 when 105 peopledied from DEG poisoning. DEG is a highly toxic organic solvent that causes acute renalfailure and death when ingested. It had been used as a diluent for sulfanilamide. Thelegislation that was passed required that new medicines be tested for toxicity before beingput on the market. Yet reports of toxicity due to DEG continue to appear. In 1998 it wasreported that DEG-contaminated cough syrup had caused the deaths of a number ofchildren in India (8).
Public Health Programmes Using Medicines 15
Figure 2. Percentage failures in ingredient content and dissolution in quality control tests onchloroquine tablets in seven sub-Saharan African countriesSource: The quality of antimalarials. A study in selected African countries. WHO/EDM/PAR/2003.4 Donated medicines Donated medicines can fail to meet quality standards. In developing countries, for avariety of reasons (e.g. poverty, lack of relevant information or inadequate controls),medicines which are less safe and effective may be used. Potentially unsafe and irrationaldonation practices contribute to this problem. It is not uncommon for the medicines usedto have already passed the date of expiry. Such medicines may have reduced efficacy andhave started to decompose, which, in turn, leads to an increase in the numbers of adversereactions. WHO has prepared guidelines for good donation practices (9). Theseguidelines outline four core principles that need to be applied before drugs are consideredfor donation:— maximum benefit to the recipient;— respect for wishes and authority of the recipient;— no double standards in quality; and— effective communication between recipient and donor.
Medicine interactions The community in which a medicine is being used could also be subject to medicine–medicine, medicine–disease or medicine–food interactions. Many communities use alter-native systems of medicine such as herbal medicines. Interactions between alternative andmodern medicines, such as the interactions between St John's Wort and indinavir,ciclosporin and warfarin (10) are well documented. Food and alcohol habits in a commu-nity may also have an impact. Garlic has been shown to reduce the plasma level ofsaquinavir by 50%; a high alcohol intake can potentiate the effects of certain medicines.
Incorrect use of medicines Worldwide more than 50% of all medicines are prescribed, dispensed or soldinappropriately, and 50% of patients fail to take them correctly. Common types ofirrational use are: 16 Public Health Programmes Using Medicines
— the use of too many medicines per patient (polypharmacy);— inappropriate use of antimicrobials, often in inadequate dosage and frequently for — overuse of injections when oral formulations would be more appropriate;— failure to prescribe in accordance with clinical guidelines; and— inappropriate self-medication, often using prescription-only medicines.
2.2.4 Health-care provider In response to the increasing recognition of deficiencies in the provision of health care byexisting health services, the concept of delivery of primary health-care by trained non-medical, village workers and involvement of the community has emerged. This hasresulted in better implementation of national PHPs. However, there is frequently aninadequate understanding of adverse reactions even among highly trained personnel andmore attention needs to be given to pharmacovigilance training in the curricula formedical and nursing undergraduates. This training in turn needs to be passed on to thenon-medical health-care workers.
The public health staff responsible for the dispensing of medicines and the monitoring ofresponses are most often paramedics with educational levels that range from primaryschool to university graduate. Their training involves education in public health issuessuch as sanitation, nutrition, hygiene, family planning and on their role in theimplementation of various programmes. They lack training in the early detection andreporting of ADRs.
Non-medically trained personnel may be unable to distinguish a medicine-inducedadverse effect from a disease or medical condition due to lack of knowledge of thecondition and of the medicine being used. In a pilot study of the use of communityvolunteers to distribute azithromycin for trachoma control in Ghana, the trainedcommunity health workers were noted to have a potential role in identifying activetrachoma. The concept of adverse effects was however a new one to most volunteers.
When adverse events were reported at follow-up visits, the volunteers had difficulty indistinguishing patients with persistent or potentially more serious events from those inwhom symptoms had abated or were abating (11).
2.2.5 Health-care system Weaknesses in health-care systems and a shortage of resources lead to underdevelopedmedicine control systems, unqualified health workers (with no medical background oreven specific programme-related training) and poor medical services. A weak regulatorysystem may also fail to prevent the availability of substandard or counterfeit medicines.
Facilities are usually lacking for performing laboratory tests that may help in diagnosingADRs, for example, blood tests for anaemia, depression of white blood cell count orabnormal liver function. Due to lack of laboratory facilities, patients at risk of ADRssuch as those associated with glucose-6-phosphate dehydrogenase deficiency may receivemedicines which are contraindicated because the prescriber may be unaware of thepatient's underlying condition. As a result, the emphasis needs to be on clinicalobservation for suspected adverse reactions.
Public Health Programmes Using Medicines 17
2.3 Public health programmes for disease control (see Figure 3)
WHO plays an important role in the initiation, conduct and evaluation of PHPsand much effort is made to select, procure and distribute medicines, train staff andto educate the community to enlist their participation. Decisions to start programmes for public health are taken after considerable deliberationat the international and national levels. These PHPs are considered crucial for reducingmortality and morbidity. A significant part of the programme budget is allocated to theprocurement of medicines.
WHO plays an important role in the initiation, conduct and evaluation of PHPs.
Numerous guidelines are produced by WHO or by Member States describing proceduresfor implementation and monitoring of PHPs and much effort is made to select, procureand distribute medicines, train staff and to educate the community to enlist theirparticipation. Detailed manuals are available on the practical procedures for the handlingand use of the medicines or vaccines, particularly storage, administration and PROGRAMME MANAGERS LOCAL COORDINATOR FOR HEALTH PROGRAMMES Figure 3. Organization of public health programmes 18 Public Health Programmes Using Medicines
contraindications. Each programme has a standard therapeutic protocol following WHOtechnical guidance. Guidelines and training programmes facilitate the proper conduct ofthe PHPs.
The framework for evaluation of each programme is generally based on anepidemiological survey. The evaluation of success of PHPs is based mainly on theestimation of changes in the incidence and prevalence of the target disease, on themorbidity and mortality data and on the number of patients treated and the number ofmedicine units delivered.
It is usual for a PHP to have a vertical organization and to be operated by a programmemanager. Programme managers in charge of different programmes do not necessarilycollaborate. At the community level however, health professionals or community agentsmay be involved in several PHPs.
2.4 Future needs of public health programmes
The large population covered and the use of new medicines provide, at the sametime, the potential for benefit and for harm. The possibility of harm is high,especially if adverse reactions are not monitored by a strategy aimed at goodreporting and early detection, review and management. In recognition of the various shortcomings, deficiencies and problems of implementingPHPs, newer strategies are being developed and global resources are being invoked. PHPsare evolving from disease control towards eradication. This is being accomplished byincreasing the coverage of the population with mass treatment, using new medicines withgreater benefits to more patients and using public-health-friendly regimens. Examples ofthe latter include oral administration and treatment with fewer doses. New medicines areproving effective where previously there has been resistance to treatment. There is alsoimproved access of populations to medicines, thanks to donations by internationalagencies and other donors. Resource-poor countries with relatively poorly developedpublic health systems, ineffective medicine regulatory agencies (MRAs) and little or nopharmacovigilance are being included in the global initiatives for disease control. There istherefore a need to ensure that cheap or donated medicines are of good quality and areeffective.
In the past, most medicines and vaccines used in public health for the control, treatment,prevention and eradication of disease were well known and had been in use for manyyears. Now new and more potent medicines with a potential for better control of diseases of public health importance are increasingly likely to be used. More diseaseswill come under public health management and as experience is gained, currentrestrictions on use may be relaxed (e.g. praziquantel in pregnancy) (12). The largepopulations covered and the use of new medicines provide, at the same time, the potentialfor benefit and for harm. The possibility of harm is great, especially if adverse reactionsare not monitored by a strategy aimed at good reporting and early detection, review andmanagement.
With increasing population coverage, the chances of developing adverse reactions andinteractions will increase, as programmes are extended to the more "vulnerable" Public Health Programmes Using Medicines 19
populations such as the young, the elderly, pregnant women and people with malnutritionand disease. In addition, health practitioners and the public need more information aboutthe potential benefit, rationality of use and risk of the medicines given.
Currently a significant proportion of episodes of tropical disease in countries where theyare endemic are treated outside the formal health sector. To respond to this situation, avariety of new health providers are being used to dispense medicines including drugsellers and traditional healers. The pharmacovigilance systems need to recognize thistrend and expand to the most peripheral level as the delivery system for drugs expands.
The public health programme manager (PHPM) has traditionally collected data onmorbidity, mortality, incidence and prevalence of disease, and on control and prevention.
He or she will now face the continuous challenge of having to evaluate the benefitsaccruing from medicine use and the risks involved.
The public health team and the PHPM will have to know about the risks of adversereactions, their diagnosis, reporting and management. They will have to deal confidentlywith the occurrence of serious and/or unexpected adverse reactions and contribute to theeffectiveness–risk assessment and any subsequent decision-making process.
20 Public Health Programmes Using Medicines
Pharmacovigilance is the science and activity relating to the detection, assessment,understanding and prevention of adverse effects or any other possible medicine-related problems (13).
3.1 Origins of pharmacovigilance3.2 Aims3.3 The cost advantage3.4 Current practice3.5 Good pharmacovigilance practice 3.1 Origins of pharmacovigilance
The history of pharmacovigilance goes back more than 40 years. In 1965 the eighteenthWorld Health Assembly, WHA 18.42, drew attention to the problem of adverse drugreaction monitoring and following further resolutions (see Annex 3) in 1966, 1967 and1970 the International Drug Monitoring Programme came into being. In 2005, 78 member countries are participating in this Programme and the last decade has seen the participation of numerous developing countries. The programme functions on thebasis of national pharmacovigilance centres coordinated by the WHO Programme forInternational Drug Monitoring, which consists of the WHO Collaborating Centre forInternational Drug Monitoring, Uppsala and the Pharmacovigilance Department of WHO,Geneva.
Recently, the concerns of pharmacovigilance have been widened to include herbal,traditional and complementary medicines, blood products, biologicals, medical devicesand vaccines. Many other issues are also of relevance to the science ofpharmacovigilance. These include substandard medicines, medication errors, lack ofefficacy, use of medicines for indications that are not approved and for which there isinadequate scientific basis, case reports of acute and chronic poisoning, assessment ofmedicine-related mortality, abuse and misuse of medicines, and adverse interactions ofmedicines with chemicals, other medicines and foods and drinks.
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;— detect problems related to the use of medicines and communicate the findings in a — contribute to the assessment of benefit, harm, effectiveness and risk of medicines, leading to the prevention of harm and maximization of benefit; — encourage the safe, rational and more effective (including cost-effective) use of — promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public.
3.3 The cost advantage
A medicines monitoring system is an essential and cost-efficient means of detecting andminimizing injury to patients and averting potential disaster. Pharmacovigilance can helpto better assess and communicate information on the effectiveness and risks of medicinesand to educate and inform patients. It is also an insurance against the undetected use ofineffective, substandard or counterfeit medicines, thus minimizing the possibility ofwastage of resources. The cost of a pharmacovigilance system, compared with the cost ofADRs to a nation and to the total national expenditure on medicines, is small (seeIntroduction). The idea that pharmacovigilance is a luxury, affordable only in thedeveloped world, should be replaced by the realization that a reliable system ofpharmacovigilance is essential for the rational, safe and cost-effective use of medicines inall countries and consequently for public health, and should produce clear advantages inrelation to cost.
Pharmacovigilance has developed and will continue to develop in response to the specialneeds and according to the particular strengths of members of the WHOPharmacovigilance Programme. The ultimate benefit is the safe, rational and effective useof medicines by patients.
3.4 Current practice
The success or failure of any pharmacovigilance activity depends on the reportingof suspected adverse reactions. 3.4.1 Spontaneous reporting3.4.2 Other methods of collecting safety data3.4.3 National pharmacovigilance centres3.4.4 WHO Programme for International Drug Monitoring 3.4.1 Spontaneous reporting The definition of spontaneous reporting is as follows: "A system whereby case reports ofadverse drug events are voluntarily submitted by health professionals and pharmaceuticalcompanies to the national pharmacovigilance centre." The success or failure of any pharmacovigilance activity depends on the reporting ofsuspected adverse reactions. To date, the mainstay of pharmacovigilance has beenspontaneous reporting by health professionals. To detect the full spectrum ofcomplications from pharmaceutical treatment and to gain a representative picture, allsectors of the health-care system need to be involved. This includes public and privatehospitals, general practice, pharmacies, nursing homes, retail dispensaries and providersof traditional medicine. Wherever medicines are being used, there should be a readinessto observe and report unwanted and unexpected medical events.
Reports made by a health professional are an interpretation of information originallyprovided by a patient who has experienced the actual benefit or harm of a medicine taken. It may also be the result of a direct observation of the effect of a medicine.
Patients who suspect they have been affected by a reaction to a medicine are normallyencouraged to inform their health professionals to enable them to report to thepharmacovigilance centre. In a few countries the national reporting system provides someopportunity for patient reporting. This is of particular value where there are disease-specific control programmes in operation.
3.4.2 Other methods of collecting safety data There are various other pharmacoepidemiological methods of collecting safetyinformation. More systematic and robust epidemiological methods that take into accountthe limitations of spontaneous reporting are required to address important safetyquestions. They need to be incorporated into postmarketing surveillance programmes.
A number of countries have implemented active surveillance systems to complementspontaneous reporting. Examples of such systems are:— prescription event monitoring (PEM) in New Zealand and the United Kingdom;— record linkage; and— case-control studies.
3.4.3 National pharmacovigilance centres National pharmacovigilance centres are responsible for:— promoting the reporting of adverse reactions;— collecting case reports of adverse reactions;— clinically evaluating case reports;— collating, analysing and evaluating patterns of adverse reactions;— distinguishing signals of adverse reactions from "noise";1— recommending or taking regulatory action in response to findings supported by good — initiating studies to investigate significant suspect reactions;— alerting prescribers, manufacturers and the public to new risks of adverse reactions; — sharing their reports with the WHO Programme for International Drug Monitoring.
National centres have played a significant role in increasing public awareness of issuesrelevant to the safety of medicines. As a result, in some countries, pharmacovigilance isincreasingly being seen as much more than a regulatory activity as it also has a major partto play in clinical practice and the development of public health policy. This developmentis partly attributable to the fact that many national and regional centres are housed withinhospitals, medical schools or poison and medicine information centres and are incollaboration with a Medicines Regulatory Authority (MRA). The scope of activities ofnational centres has expanded to include communication of information about the benefits,harm and effectiveness of medicines to practitioners, patients and the public.
In the nature of their work, national centres have also become familiar with real orcontrived medicine scare crises, which they have managed with variable success.
1 Noise is defined as the information which is not part of a signal or which interferes with or obscures a signal.
3.4.4 WHO Programme for International Drug Monitoring National pharmacovigilance centres are functioning as an international networkcoordinated by the WHO Programme for International Drug Monitoring. The Programmehas achieved much in improving the activities, support and recognition of individualnational pharmacovigilance centres. It plays a key role as a communication and trainingcentre and clearing-house for information on the safety of medicines. The WHOCollaborating Centre for International Drug Monitoring in Uppsala, Sweden manages theinternational database of adverse reaction reports received from national centres. In 2005this database held over 3.5 million case reports. The majority of contributing nationalcentres have ready electronic access to these. The Centre has established standardizedreporting by all national centres and has facilitated communication between countries topromote the rapid identification of signals. The terminologies developed within the WHOprogramme for coding adverse reactions to medicines have been widely adopted bynational centres, manufacturers and medicine regulators.
More effective communication of information is being promoted and encouraged throughthe WHO Programme for International Drug Monitoring (14, 15). 3.5 Good pharmacovigilance practice
To attain a coherent pharmacovigilance system it is vital that guidelines andstandards are developed, which describe the practical details of the intendedinformation flow. Effective pharmacovigilance relies on contributions by many people with varyingeducational backgrounds. The concept of pharmacovigilance is normally not wellunderstood, either by health professionals, patients or the general population. To attain acoherent pharmacovigilance system it is most important that guidelines and standards aredeveloped, which describe the practical details of the intended information flow. Suchstandard operating procedures should include information on the following: — What constitutes a reportable adverse reaction?— Who is expected to report an observation of a suspected medicine-related problem?— The availability and practicalities of filling in a reporting form.
— Procedures for submission or collection of reports.
— Routines for assessment, follow-up and processing of case reports at the — Procedures for analysis of aggregated information and options for action.
— Good communication practices.
— A description of indicators by which the progress of the monitoring system may be Pharmacovigilance guidelines are the main materials available for use in the training ofperipheral health workers in pharmacovigilance (3, 13, 17, 18).
4.1 Effectiveness and risk: benefit and harm4.2 Decision-making in risk situations4.3 Good decision-making practices 4.1 Effectiveness and risk: benefit and harm
Estimating the risk and benefit of medicines among the populations exposed tothem is essential to promote their rational and safe use and will enhance thetolerability and acceptability of mass-treatment programmes. The effectiveness and risk profiles of many of the medicines used in PHPs in the pasthave been established by long experience rather than on the basis of epidemiologicalevidence. The modern approach to public health requires that advice be given on the bestgeneral ways of approaching the management of diseases, notwithstanding the necessityfor considerable freedom to modify therapy according to individual needs. Because of theneed for comparative effectiveness and risk profiles of treatment options to find the mostuseful medicine at the most reasonable cost, it is necessary to use the correct conceptualand 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 subjectswho have received the medicine in randomized clinical trials before it is marketed may beas few as 100 and is never more than 5000. Although such trials are an irreplaceable toolfor determining the potential benefits of the medicine, they provide only limited insightinto the likely responses of patients in whom other medicines are administeredconcurrently; the effects on diseases other than the target disease; the effects of dosevariation; nutrition, and many other factors. In clinical trials, only risks of greater than1/1000, at best, are likely to be noted. At this stage it is not possible to say that degreesof 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 tensof thousands of unselected patients have been treated, and information on the results hasbeen gathered.
It is also important not to confuse benefit with effectiveness. Benefit, described as anoverall good, is difficult to define for a society.
It is common to compare pre-marketing efficacy with the spontaneous reports of harmcollected. Because the processes for collecting the information are totally different, greatcare must be taken in interpreting the results; indeed many assumptions need to be madebefore any intepretation is possible. Another common problem is the comparison of theefficacy and harm of a new medicine with what is much closer to a set of effectivenessand risk data for an older medicine, derived over years of experience.
Effectiveness and Risk Assessment of Therapies 25
The Council for International Organisations of Medical Sciences has produced amonograph (19) that gives much helpful practical advice on how to assemble informationon both effectiveness and risk, and points out some of the potential pitfalls in evaluation.
It proposes that the context of the evaluation should be quite clear and that any valuejudgements must be transparent. Nevertheless, the likely imbalance between theeffectiveness data and risk data in terms of quantity, quality and the sources, remains adifficulty that is rarely addressed explicitly in comparative studies of therapies, whetherpharmaceutical or other (such as surgery).
Therefore, as medicine development progresses at a rapid pace, and WHO proactively, inpartnership with industry, promotes the use of new medicines for the control of diseasesin developing countries, there will be a paradigm shift in approach to ADR monitoring ofmedicines used in national programmes.
Estimating the risk and benefit of medicines for the populations exposed to them isessential to promote their rational and safe use and will enhance the acceptability andtolerability of mass-treatment programmes. This estimation requires the monitoring ofprogrammes to detect, evaluate and prevent adverse reactions, including effects onpregnant women, the elderly and children. Acceptance, misuse, pharmacologicaldependence, therapeutic errors, and therapeutic failures due to poor-quality medicine orcounterfeits, all need to be evaluated to judge the efficiency of the treatment.
4.2 Decision-making in risk situations
A concept central to decision-making is "acceptable risk". The fundamentalquestion is, "Acceptable to whom?" In critical public health situations, decisions are made either by the PHP or by thenational regulator on the basis of available evidence, informed by prior experience,political context and professional judgement.
The decision could be any of the following:— Stop the programme; investigate effectiveness/risk.
— Continue the programme, but investigate effectiveness/risk.
— Undertake additional studies.
— Issue information of public interest.
— 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 afterdiscussion with his or her patient. The prescribing physician and the patient must still beat liberty to make their choice, although their decisions should be guided by the publichealth constraints specific to that locality, and based on reliable information.
In public health and community health issues, the manufacturer is responsible for makingthe medicine available to people, and regulators are responsible for protecting andadvancing the health of the public. The latter may be considered to have consentedimplicitly to such decision-making, but individuals in the community are less well- 26 Effectiveness and Risk Assessment of Therapies
informed. The assessment of effectiveness and risk is therefore even more critical, and islikely to be challenged by individual accounts of benefit and harm, particularly if they areemphasized by the public media.
4.3 Good decision-making practices
The conventional decision-making process in public health needs to be strengthenedto deal with quantitatively and qualitatively more complex issues arising out of newmedicines being used in PHPs. 4.3.1 Expertise4.3.2 Evidence base and scientific decision-making4.3.3 Explicit predetermined criteria4.3.4 Comparators4.3.5 Objectivity4.3.6 Transparency4.3.7 Accountability Decision-making is the process of determining the actions to be taken, who should takethem, and the order and methods of taking action. It also entails judgements on the bestmeans of monitoring, follow-up and of communicating the appropriate information to theparties concerned. Decision-making, should follow three principles, namely:— objectivity;— transparency; and— accountability.
Moreover, to achieve success, there is a need to consider each decision in terms of thefollowing headings:— Obtaining the best data and information— The context of the decision— Definition 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 smallerdecisions into an overall strategy — Communication and action— Follow-up— Impact— Revision of the original decision as necessary.
Regulators and manufacturers make decisions on the marketing or withdrawal ofmedicines, or changing the label or summary of product characteristics. This is oftendone in consultation with a team of experts either as a standing committee or an ad hocexpert committee. Consumers and patients may be directly or indirectly party to thedecision or may not be involved at all.
The decision to start a programme for public health is taken after considerabledeliberation at the international and national levels. The regulator (medicine controller) or manufacturer has not usually been involved until now, because the medicines usedhistorically have been marketed for a long time. Also, in developing countries, consumers Effectiveness and Risk Assessment of Therapies 27
are usually not involved directly in the decision-making process. However they influencethe success of the programme by accepting or rejecting it as it begins to have an impacton them.
The conventional decision-making process in public health needs to be strengthened todeal with quantitatively and qualitatively more complex issues arising out of newmedicines being used in PHPs. It is important that all the relevant players are identifiedand involved from the start and that procedures are outlined to enable those involved toreach the best decision.
4.3.2 Evidence base and scientific decision-making Information should be gathered from all relevant sources and by a variety of methods.
The data from all sources including initial regulatory applications, scientific publications,and information on populations exposed in different countries, among others, should bemade available as completely and rapidly as possible. Computer programmes forcollection and collation of data are needed to optimize data-gathering. Computer-assistedalgorithms, when used appropriately, may assist in the consideration of all available data,weighting it and making the system transparent and objective.
4.3.3 Explicit predetermined criteria International agencies such as WHO would play a key role in developing predeterminedcriteria for decision-making. When a new medicine is made available for public health,the efficacy and hazard data would be based on pre-marketing studies. However, once theuse of a medicine has become widespread, the effectiveness–risk profile might be verydifferent. A risk-management strategy (including assessment of effectiveness in practice)will help in making decisions, which may well vary from region to region due to regionaldifferences in distribution of pathogens, disease presentation or perceived importance(priority) of the disease in relation to other health-related issues.
4.3.4 Comparators Data on experience with other therapies including non-medicine interventions to assesscomparative effectiveness and risk are essential to enable decisions regarding newmedicines and programmes to be made. In the case of new medicines to be used for thetreatment of an infectious disease, information on the effectiveness and risk of themedicines in use would be needed. Such information is usually collected in situationswhere its generalization to another context needs to be considered carefully. If medicinesare to be used for the control of a disease, when there is no existing programme,information on the natural history of the disease together with morbidity and mortalitystatistics will be required.
However once the programme is implemented, especially if it is implemented in an entireregion, data on comparators will not be available and it would be necessary to rely onhistorical data for comparison. For anti-infective agents the effectiveness and risk balancecould change due to alteration (or even return) of bacterial sensitivity or resistance.
28 Effectiveness and Risk Assessment of Therapies
4.3.5 Objectivity Objectivity relies on several attributes and qualities of people and processes. Of these, awillingness to be open with information and details of processes, identifying all theplayers who need to be included and involving them, identifying and separating fact fromopinion, are key factors.
4.3.6 Transparency It is expected that in the decision-making process, information on the options availablewill be considered objectively, and be made openly available for critical review.
4.3.7 Accountability All partners in the process, including pharmaceutical manufacturers, regulators, managersof PHPs and pharmacovigilance experts are involved in ensuring the success of the PHP.
Decisions are made on the basis of data available at a given time and should be madeobjectively. Circumstances change; therefore the expected outcomes must either bespecified or estimated. After an action has been initiated, data must continue to becollected as part of the continuous process of monitoring of effectiveness and safety.
The data should be periodically analysed to determine whether:— the outcomes are those desired;— new information indicates the need for further review and possible modification of the — there are sufficient data to consider undertaking a new effectiveness–risk assessment.
Effectiveness and Risk Assessment of Therapies 29

There can be better health outcomes as a consequence of good information onsafety, which allows the early identification and prevention of adverse reactions,resulting in the more rational use of medicines, and better adherence within thetarget population. 5.1 Strengths5.2 Weaknesses Recently there have been some initiatives within countries, or under the leadership ofWHO, to create and develop subsystems for pharmacovigilance to monitor the specificproducts used in their PHPs (e.g. vaccines, antiretroviral therapy, antimalaria programmesand anthelminthic programmes). On the other hand, some developing countries alreadyhave established pharmacovigilance centres that function independently. This situationprovides all the ingredients for developing a unique and efficient pharmacovigilancesystem within PHPs and to integrate both systems.
Although there are fundamental limitations and weaknesses in both PHPs andpharmacovigilance systems, PHPs have some distinct advantages for undertakingpharmacovigilance, and pharmacovigilance systems can benefit from the experience ofPHPs.
Public health programmes:— often have well-established roles through undertaking important and essential health care work with large populations, often engaging in preventive and curativeinterventions through the use of medicines; — frequently get better resource support than is normally given to pharmacovigilance programmes including support from international sources; — normally have set guidelines or protocols;— adhere to established performance monitoring and evaluation procedures;— have established information systems to process epidemiological data;— can often provide denominators (numbers of patients treated) which can be used for the calculation of rates or incidence of ADRs; and — have good training programmes for health care providers.
The particular strengths of pharmacovigilance programmes are in the development of newmethods for assessing the safety of medicines, including better analyses of data andsignal-detection processes. As well as safety issues, pharmacovigilance programmesassess quality and efficacy and the correct indication(s) for use. All of these can providecritical support for the use of a specific medicine, often lacking in PHPs. Anotherstrength of pharmacovigilance programmes of considerable importance to PHPs is thetraining and expertise in effectiveness–risk evaluation and its communication to the 30 Pharmacovigilance and Public Health Programmes: Current Situation
EXISTING SYSTEMS National PV centre Figure 4. Pharmacovigilance and public health programmes: current systems population, which is an essential component of good pharmacovigilance practice and isan ethical imperative (14).
There is clearly considerable merit in linking pharmacovigilance with PHPs. There can bebetter health outcomes as a consequence of good information on safety, while the earlyidentification and prevention of adverse reactions results in the more rational use ofmedicines and better adherence within the target population, as a result of the reassurancethat monitoring and good communication on risks and benefits provides. Theidentification of safety, efficacy and quality problems will also have favourableimplications for decisions on medicine procurement. In addition, resources andinformation can be shared and duplication of effort can be avoided.
Harmonizing these programmes should strengthen the national health authority and healthcare delivery systems as a result of better health outcomes from the PHPs and resourcesavings. There are also opportunities for shared capacity building and the conduct oftrials of new medicines used in PHPs. In addition, the effectiveness of pharmacovigilancewill be enhanced because of the availability of denominator values and the ability tocalculate the actual risk of harm and make better comparisons between medicines.
Although PHPs are well-established and are considered as crucial and essential for thehealth of any nation, pharmacovigilance often remains incorrectly perceived as a luxury Pharmacovigilance and Public Health Programmes: Current Situation 31
discipline that governmental authorities cannot support and hence that only developednations can afford. In most developing countries, there are insufficient resources withinthe public health system to undertake training and capacity building and to invest insystems for monitoring drug efficacy and safety. The major resources are oftenconcentrated on developing PHPs to reduce disease morbidity and mortality and very few of these countries have a well-established pharmacovigilance system.
In most cases, PHP managers are neither aware of nor trained in the need to detect andreport adverse reactions to the medicines that are used in their programmes and that havebeen on the market for a long time. It is assumed that the medicines used are universallysafe and that there is therefore no necessity to monitor or to re-evaluate them. Staffworking within PHPs in most developing countries are not trained to assist in monitoringthe safety of medicines.
In reality, the implementers of PHPs are often not interested in ADR monitoring, or mayunderplay the significance of adverse reactions to project the safety of medicines andensure good adherence. To discuss ADRs is perceived to have a negative impact on thePHP. Training and information about the detection and management of ADRs are seldomconsidered or emphasized and programmes rarely include any evaluation of benefit versusharm. For example, the manual for the revised national Tuberculosis Programme givesonly a table for possible ADR symptoms (side-effects of antituberculosis medicines) andaction to be taken.
PHP managers do not always collaborate with pharmacovigilance centres or other PHPsand often function independently of each other leading to duplication of effort and a lack of harmonized terminologies, data collection methods and causality assessment.
The information that is collected is not added to the international database forpharmacovigilance and therefore the international community derives no benefit from it.
Furthermore, medicine regulators do not always have the benefit of feedback concerningmedicines used in PHPs.
In general, pharmacovigilance is not seen as a component of public health. The reasonsfor this include a misunderstanding of the meaning and the objectives of the discipline;the absence of facilities for receipt, management and analysis of reports; and lack of areporting culture. It is hoped that this document will encourage clinical programmemanagers to develop a comprehensive understanding of the importance ofpharmacovigilance.
32 Pharmacovigilance and Public Health Programmes: Current Situation

6.1 Introduction6.2 Justification6.3 Requirements for pharmacovigilance in public health6.4 Spontaneous reporting6.5 Cohort event monitoring6.6 Roles and responsibilities6.7 Where there is no national pharmacovigilance system6.8 Training and capacity building6.9 Evaluation of the system It is important to emphasize that the survival of a PHP may depend on goodpharmacovigilance. The specific needs of countries and programme managers in public health for theirpharmacovigilance programmes will differ as new initiatives are undertaken, and theefforts required will depend on the existing systems and infrastructure. It is important toemphasize that survival of a PHP may depend on good pharmacovigilance.
Some countries have well-developed, functioning, national pharmacovigilance centres,which are backed by an MRA. In such countries there is also a strong public healthdepartment with separate staff dealing with each vertical disease-related programme. In other countries, the public health department may employ the same staff to handledifferent disease programmes and pharmacovigilance centres may be rudimentary orabsent.
National pharmacovigilance centres may be centralized or decentralized. In differentcountries public health departments may function at different levels such as the primary,district, state and/or country levels.
The pharmacovigilance in public health model needs to be robust and flexible if it is tobe implementable not only in countries with pre-existing public health andpharmacovigilance systems, but also in countries with weak or deficient public health andpharmacovigilance programmes. The pharmacovigilance in public health model shoulddraw on the strengths of the pharmacovigilance and PHPs, avoiding duplication. Themodel should emphasize sharing of human resources and the expansion of knowledge oneffectiveness/risk, collaboration, effective communication, integration, training andcapacity building.
Integration of Pharmacovigilance into Public Health Programmes 33

National PV centre INVESTIGATION TEAM Figure 5. Integration of pharmacovigilance into public health programmes Adverse reactions are a significant cause of morbidity and mortality and can affectadherence to treatment schedules and increase the risk of resistance and relapse ofthe disease. The use of pharmaceutical preparations is one of the fastest-growing components ofhealth care expenditure throughout the world. It accounts for 30% of the total healthbudget in many countries. At the same time, adverse reactions are a significant cause ofmorbidity and mortality. They can affect adherence to treatment schedules and increasethe risk of resistance and relapse of the disease. The treatment of ADRs imposes a largelyunrecognized, but considerable, financial burden on health care due to the need forhospital care or other medical interventions. Some of this cost to national health budgetsand the personal cost, both financial and in terms of suffering, is avoidable. Health-carepractitioners are in a position to make good use of both the positive and negativeexperiences of treatment to contribute to medical science and to an improvedunderstanding of diseases and medicines.
In some countries there are now high public expectations for the safe delivery of health care, but the public rarely recognizes that pre-approval studies are not sufficient totruly characterize the effectiveness and risks of pharmaceutical products. Goodpharmacovigilance practice can generate the evidence that will inspire public confidenceand trust.
34 Integration of Pharmacovigilance into Public Health Programmes
6.3 Requirements for pharmacovigilance in public health
The ultimate goal is the success of the public health programme. 6.3.1 Reporting, data collection, investigation and management of adverse reactions6.3.2 Coordination6.3.3 Database, causality (relationship) assessment and data analysis6.3.4 Special situations6.3.5 Decision-making6.3.6 International linkage The major aims of pharmacovigilance in public health will be the same as those of thenational pharmacovigilance centre. These are:— rational and safe use of medicines by health professionals;— assessment and communication of the risks and effectiveness of medicines used; and— educating and informing patients.
The ultimate goal is the success of the PHP.
The means of achieving these goals will need to take into account the peculiarities andstructure of the PHPs. Pharmacovigilance systems should have the capability for thefollowing important functional components:— receiving and processing of reports (with verification, interpretation, coding of medicines and ADRs, and case causality assessment) and case management; — establishing databases and procedures for data analysis and review;— signal detection;— decision-making, risk management, follow-up;— good communication;— coordination between pharmacovigilance, regulatory and public health activities;— training of health care workers in reporting adverse reactions;— training in all aspects of pharmacovigilance;— promotion; and— international linkage.
The pharmacovigilance in public health plan for a country should address thesefunctional requirements, give details of the flow of data including feedback, and produceclear organigrams specifying roles and responsibilities. The actual designations of staff,physical locations, exact levels of responsibilities (e.g. national, state, district, primaryhealth centre, village) will vary between countries and will depend on existing health careand regulatory structures in the country.
6.3.1 Reporting, data collection, investigation and management of adverse reactions Public health departments usually have disease-specific programmes with dedicated staff.
Programmes are generally implemented through health-care workers at the village level,who are supervised by the programme-specific staff. Pharmacovigilance programmes inpublic health should function optimally by utilizing this infrastructure with appropriateadditions as necessary. The essential players should be: Integration of Pharmacovigilance into Public Health Programmes 35
— patients (see section 6.6.1);— primary health-care workers/professionals (see section 6.6.2);— district hospital (see section 6.6.4);— district health officer (see section 6.6.4);— district investigation team (see section 6.6.4);— tertiary care referral hospital (see next paragraph and section 6.7);— programme manager (see section 6.6.4);— national pharmacovigilance coordinator/pharmacovigilance centre (see section 6.6.5 and section 6.6.8); and — expert safety review panel (see section 6.3.3).
Their roles are described in the sections referred to and in Annex 1.
The village health worker or the physician at the primary health-care centre, together withthe district health officer or programme manager, and the tertiary care referral hospital,would form the unit responsible for detecting, investigating, managing and reportingADRs. The district health officer or programme manager should coordinate this activity.
It is critical that ADRs be reported without delay.
A standardized reporting form should be available to the primary health-care worker. Thisperson should report the ADRs to the district health officer (or equivalent). The districthealth officer or programme manager in association with the district investigation teamwill follow up reports of serious ADRs or other ADRs of interest and submit details tothe national pharmacovigilance coordinator for review by the safety review panel.
The primary health-care worker should manage minor suspected ADRs. Patients withserious or severe ADRs should be referred immediately to the nearest hospital (districthospital) for investigation and management. The details of management and outcomeshould be included in the report submitted by the district health officer or programmemanager. Staff from the PHP already performing the function of health-care deliveryshould be best suited to detect, investigate and manage ADRs. These staff would howeverneed extra training in the identification and reporting of ADRs.
6.3.2 Coordination The essential elements of pharmacovigilance in public health are the same as forpharmacovigilance in general. Essential to the success of pharmacovigilance in publichealth is a pharmacovigilance coordinator who will bring the relevant expertise andcoordinate and integrate the pharmacovigilance activity between different verticaldisease-specific PHPs.
The position of coordinator may be full-time, or initially part-time, depending on theextent and nature of development in the country, and the person appointed should be amember or secretary of the expert safety review panel (ESRP). The coordinator should bedrawn from the national pharmacovigilance centre. Where no such centre exists, anydedicated medical person from an academic institution, public health or the MRA mightmanage this activity, but should have a scientific approach. He or she may be locatedphysically in a university hospital or a public health department with the necessaryinfrastructure and secretarial assistance to enable him or her to carry out his or her duties.
This person should be knowledgeable about pharmacovigilance concepts and would be a 36 Integration of Pharmacovigilance into Public Health Programmes
useful resource officer to develop a national pharmacovigilance system according tointernational standards.
6.3.3 Database, causality (relationship) assessment and data analysis The databaseRelationship/causality assessmentData analysisThe expert safety review panel Reports of adverse reactions should be submitted by the district or programme officers to the coordinator for inclusion in the database. The database should have all the fieldsnecessary for adequate case assessment, accurate analyses and possible follow-up. Theseshould include:— location of origin of the report;— the identity of the reporter;— patient identification — to avoid duplication and enable follow-up if necessary (the patient must be identified in such a way as to ensure patient confidentiality); — age and sex of patient;— information concerning the medicine, including name and formulation, manufacturer, mode of administration, dose and dates of administration; — indication for use;— other morbidity and relevant history;— concomitant medications with doses, dates and indications;— details of the event(s) with date of onset and details of any investigations;— adverse reaction term from a recognized dictionary, e.g. the WHO Adverse Reaction Terminology (WHO-ART) or the Medical Dictionary for RegulatoryActivities (MedDRA); — assessment of seriousness and severity; and— management and outcome.
Relationship or causality assessment The relationship or causality assessment should follow the WHO Guidelines (3). Theinitial step is to establish the temporal relationship of the event to the use of themedicine. This requires knowledge of the duration to onset of the event from the time ofcommencing treatment with the medicine, the response to withdrawal of the medicine andthe result of rechallenge if this is undertaken. Causality for a particular type of event canoften be established only by epidemiological means and/or a knowledge of thepharmacology of the medicine. In the context of PHPs for disease control, it is necessaryto record all events that could possibly be related to the medicine. It is for thepharmacovigilance centre to assess causality.
The numbers of reports of particular events can be used to calculate incidence if thedenominator is known. Programs should be available that will sort the data appropriately,e.g. different types of event by System Organ Class, or to enable analyses of possible riskfactors such as age.
Integration of Pharmacovigilance into Public Health Programmes 37
The expert safety review panel The ESRP occupies a very special position in causality assessment. A preliminaryassessment should have been undertaken and follow-up conducted if necessary, before reports are presented to the ESRP.
The panel should be constituted as follows:— the programme manager;— the pharmacovigilance coordinator;— a clinical pharmacologist or a clinician who has an interest in medicines;— a physician and disease expert;— a pharmacist;— a member of the MRA;— other members with specific expertise as required e.g. a paediatrician or a gynaecologist; and — a representative of a consumer organization may be included.
The functions of the ESRP will be to:— review reports referred by the pharmacovigilance coordinator or programme manager;— assess safety issues from reports of serious ADRs and/or cumulative data;— assess safety issues that, although not serious, may affect adherence;— assess reports that may suggest lack of efficacy and determine the likely cause;— recommend further follow-up and investigation when indicated; and— recommend appropriate action to the pharmacovigilance coordinator, programme manager or regulatory authority. This will include communication with healthproviders and/or the public.
The ESRP may be common to all PHPs or may be disease- or programme-specific.
The facilities of the national pharmacovigilance centre for the assessment of case reports,data processing and database management should be used by the coordinator, withmodifications as needed. In countries where no such system exists, the pharmacovigilancecoordinator should develop the facility with advice from WHO and the ESRP.
The recommendations of the ESRP should be submitted to the regional or nationalprogramme director, the national pharmacovigilance centre and/or the MRA for theirdecisions.
6.3.4 Special situations New medicines become available with little or no information on their safety duringuse in pregnancy in humans or on risk of death among people with the diversecharacteristics that will be seen in the target population. Exposure during pregnancy New medicines become available with little or no information on safety when used bypregnant women. To assess the safety of a medicine during pregnancy, it is essential thatall women of child-bearing age are followed up to see if they were pregnant at the timeof exposure to the medicine in question. Before administration of the medicine to a 38 Integration of Pharmacovigilance into Public Health Programmes
woman of childbearing age, questions should be asked about the possibility that thewoman is pregnant, but because many women, particularly in rural areas, may not beaware of their pregnancy in the early months, it is necessary to check later to see if theywere pregnant at the time. All women who are identified as having received the medicinewhile pregnant should be followed up for the outcome of the pregnancy, both in terms ofthe health of the fetus/infant and the mother. The involvement of antenatal clinics andbirthing units is essential. Country- and programme-specific procedures need to beestablished to collect all the relevant data. The district investigation teams should have theresponsibility for investigating outcomes and should report to the nationalpharmacovigilance coordinator. The national pharmacovigilance coordinator shouldestablish a pregnancy register and report current and cumulative results to the ESRP.
It is important that all unexpected deaths following administration of the programmemedicine are investigated. In many areas, and in the absence of routine follow-up,problems will arise in identifying these deaths, but a system of notification appropriate to the area should be established. In each case, the cause of death will need to beestablished as accurately as possible. Deaths that have occurred within a plausible timeperiod following administration of the medicine would need to be investigated further bythe district investigation team to establish the strength of the association between thedeath and the medicine. Guidelines for the follow-up of specific causes of death shouldbe formulated. All deaths considered to have a possible relationship to the medicineshould be reported to the district programme manager and thereafter to the ESRP.
6.3.5 Decision-making The reporting team, district health officer or programme manager, in consultation withthe supervisor, could decide to stop administration of the medicine to the affected patient,withhold a batch, or withhold treatment in the area as an interim measure, pending a finaldecision by the competent authority.
The MRA, with inputs from the ESRP, national pharmacovigilance centre, national PHP,WHO Collaborating Centre for International Drug Monitoring, WHO and theInternational Advisory Panel as appropriate, may give relevant advice.
6.3.6 International linkage As soon as a pharmacovigilance programme is set up in a country, efforts should be madeto link it formally with the WHO international network of pharmacovigilance centres. As of2005, the WHO International Drug Monitoring Programme, comprising 78 national pharmacovigilance centres throughout the world, maintained a databasecontaining more than 3.5 million case reports of suspected ADRs. The WHO database andthe competence, support and services offered by the WHO Programme should be used forthe development of the emerging national pharmacovigilance system. In the WHOdatabase, information from developing countries is under-represented, as is information onmedicines used in the treatment of tropical diseases. If PHPs sent all the information thatthey collected on adverse reactions to the pharmacovigilance centre in their country, thiswould then be forwarded to the WHO database. Experience gained from PHPs willconstitute a valuable contribution to this international repository. The nationalpharmacovigilance coordinator should contact WHO and establish working relationships Integration of Pharmacovigilance into Public Health Programmes 39
with the WHO Collaborating Centre for International Drug Monitoring with the aim ofattaining formal member status in the WHO Programme for International Drug Monitoring.
6.4 Spontaneous reporting
Spontaneous reporting is a system whereby case reports of adverse drug events arevoluntarily submitted by health professionals, pharmaceutical companies orconsumers to the national pharmacovigilance centre. Spontaneous reporting is defined in section 3.4.1. It is basically the reporting of asuspected adverse reaction on the initiative of the health professional who becomes awareof the problem, or on the patient's initiative. These reports can be communicated by anymeans, but in countries with a well-developed pharmacovigilance system they are mostoften reported on the country-specific reporting card. The key feature is that reports areinitiated by the health professional (or patient) and not solicited systematically. The typeof reporting described in this document so far should be considered spontaneous.
However, in PHPs, reporting should be more focused and intensive. Such reporting issometimes referred to as intensified spontaneous reporting, or ideally, prospectivemonitoring should be undertaken as described below.
6.5 Cohort event monitoring
As well as producing data on rates, cohort event monitoring is particularly effectiveat identifying previously unrecognized and unsuspected adverse reactions anddefining the associated risk factors. Cohort event monitoring refers to the use of prospective, observational cohort studies of patients to whom the medicine of interest has been administered. All adverse eventsare recorded in the study, not only suspect adverse reactions. This makes the methodparticularly effective at identifying previously unrecognized and unsuspected adversereactions. A cohort is built up of all patients receiving the medicine together withdemographic data. This requires a record of patients to whom the medicine isadministered. The means of recording this information will be best established whenplanning the PHP and may vary depending on the country (and perhaps the region), theprogramme and the medicine being monitored. Normally a cohort of 10 000 patients issufficient to provide adequate statistical power, but larger numbers may be needed toenable adequate study of particular subgroups of interest. This method has been describedas "prescription event monitoring" (PEM) (20). The term "PEM" is inappropriate for usein most PHPs and this method is better referred to as "cohort event monitoring".
Essentially the method consists of— establishing a cohort of patients; and— collecting information on all the adverse events that occur in these patients for a (defined) period after use of the medicine.
The cohort needs to be as complete and as representative as possible. Decisions wouldhave to be taken on the selection of patients. Two options are available: enrolment of allpatients in selected, representative regions until the cohort reaches the target figure, or amethod of systematically sampling patients from the whole country, e.g. recruitment ofall patients seen at clinics on a Thursday.
40 Integration of Pharmacovigilance into Public Health Programmes
The recording of all adverse events is essential if new signals are not to be missed.
Appropriate recording forms would need to be designed, appropriate proceduresestablished for follow-up to obtain information on any adverse events, and staff trained in the methodology.
The method is adaptable to different situations and different needs. One approach thatwill help reduce potential confounding is to record adverse health events experienced byeach individual for a period prior to exposure to the medicine and an equal periodafterwards (e.g. 1 month).
Cohort event monitoring has the following advantages:— the ability to produce rates;— the ability to produce a complete adverse event and/or adverse reaction profile for the medicine(s) of interest; — the ability to characterize reactions in terms of age, sex and duration to onset and thus produce risk factors. Other relevant information may be collected, for exampleon weight or comorbidity to provide the opportunity for determining other riskfactors; — the ability to make accurate comparisons between medicines using this — the ability to establish a pregnancy register and define and calculate rates of any abnormalities. To enable the identification of women who are pregnant, an appropriatefollow-up period would need to be determined (e.g. 5 months); — because of the routine follow-up, the ability to detect, with confidence, reduced or failed therapeutic effect and thus raise suspicion of inaccurate diagnosis of disease,programme failure, poor quality or counterfeit medicines; — the ability to record and examine details of all deaths; and— the ability to produce rapid results in a defined population.
These advantages help overcome the many deficiencies of spontaneous reporting onwhich the majority of pharmacovigilance activity depends. Spontaneous reportingremains essential, and because it normally covers the whole population for an unlimitedperiod, may have a better chance of revealing rare, serious ADRs. It should beremembered though, that common, non-serious ADRs can be more important than rareserious reactions, because they affect more people. The two systems of monitoring arethus complementary.
6.6 Roles and responsibilities
Where established, the national pharmacovigilance centre will be responsible forthe development of pharmacovigilance in the public health system, will promotepharmacovigilance in the PHPs and sensitize professionals and public health staffto the reporting of adverse reactions and irrational use of medicines. 6.6.1 Patients and the public Public awareness about adverse reactions, early reporting and management are essentialfor ensuring patient confidence, in and adherence to, pharmacotherapy. In some countriespatient reporting is accepted and can add value, but this needs to be separate fromreporting by health professionals. In some programmes (e.g. AIDS), the input and Integration of Pharmacovigilance into Public Health Programmes 41
involvement of patient interest groups can be sought while formulating the programmeand should be part of the feedback–communication link.
6.6.2 Primary health-care workers It is the responsibility of the primary health-care provider to detect, investigate, manageand report ADRs. These staff will need training on the importance of adverse reactions,diagnosis, the basic principles of causality assessment and the important elements of theadverse reactions reporting form.
Patient education is an important role of the primary health-care provider. Educating thepublic on ADRs is important for promoting adherence. Counselling and explanationabout adverse reactions will promote patients' confidence and adherence.
The reporting of adverse reactions needs continuous stimulation. It is important toachieve a positive attitude towards pharmacovigilance. To encourage reporting, thefollowing steps should be of help:— easy access to reporting forms;— training;— acknowledgement of receipt of a report and provision of feedback to the reporter;— participation of reporting staff in pharmacovigilance meetings, and of pharmacovigilance staff in professional meetings; and — collaboration with the national pharmacovigilance centre.
6.6.3 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 healthfacilities.
6.6.4 District investigation team The district investigation team plays a central role in monitoring adverse reactions. Theteam should comprise a clinician in the district hospital, head nurse, pharmacist anddistrict health officer or programme manager. The team is responsible for following upadverse reactions reported from all the health facilities within their district. (In the caseof vertical programmes the specific programme manager will be responsible formedicines pertaining to that programme.) The team will play an important role incollaboration with and encouragement of reporting by primary health centre staff andhospital staff. Their detailed follow-up of suspected ADRs will be used to assesscausality. The district health officer or programme manager will coordinate theinvestigation, report to the national pharmacovigilance coordinator, and contribute to theeducation of clinical staff and the public on medicine safety. The findings ofinvestigations and conclusions of the ESRP, in terms of causality and actions to be taken,will be fed back to the reporter and patients by the district investigation team ordesignated individual.
When dealing with reports of ADRs, the district investigation team should: • Review all reports.
• Decide which reports need further investigation on the basis of: 42 Integration of Pharmacovigilance into Public Health Programmes
— seriousness (including all deaths);— severity;— exposure to medicine during pregnancy;— apparent signals of new reactions; and— 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 ESRP.
6.6.5 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 coordinatorwould include coordination, communication, integration, training and supervision of thepharmacovigilance-related activities of the district investigation teams. This person wouldalso serve as member or secretary of the national ESRP. The national coordinator shouldbe responsible for developing the system, for the collection and storage of all reports ofadverse reactions and for coordination and communication between the nationalpharmacovigilance centre, the district investigation teams, the national MRA, the PHP atthe national level, the ministry of health, international centres, and the pharmaceuticalmanufacturer or supplier. The national coordinator should ensure harmonization ofpharmacovigilance in public health with other national pharmacovigilance activities,promote the reporting form, and develop a national database for signal generation. Thecoordinator should have the necessary facilities for carrying out his or her duties. In areaswhere no national centre exists, the national coordinator should be based in an academicinstitution, tertiary care hospital or in a public health office.
The coordinator should ensure that the ADR reports are processed appropriately forassessment by the ESRP. These would generally fall into one of three categories:— reports selected for investigation by the district investigation team, which should be considered in detail; — reports considered to be a signal of a new adverse reaction; and— all other reports, which may be presented in summary format, so that an overall reaction profile of the medicine can be obtained.
Depending on the volume of reports, a selection process may need to be developed sothat the ESRP can give priority to the important issues.
6.6.6 National medicines regulatory authority The regulatory authority will receive reports and recommendations from the ESRP. It willperform risk assessment and consider options for regulatory action which may involverequiring the manufacturers to make changes in the labelling of their product or may be arestriction in the use of the product, a temporary suspension or complete withdrawal. Theregulatory authority may liaise with other national MRAs and it should always pass onthe information on any action taken to WHO.
Integration of Pharmacovigilance into Public Health Programmes 43
6.6.7 Pharmaceutical industry and marketing authorization holders Pharmaceutical manufacturers are legally responsible for the safety and effectiveness ofmedicines while the product is available in the marketplace. They should providemedicines of good quality and have stewardship of their products. As essential players inthe provision of medicines, they should be kept informed of the results of monitoring andrelevant decisions. They also have a duty towards assessing the effectiveness and safety ofa PHP and the benefits to patients. They should report adverse reactions both to thenational pharmacovigilance centre (or in the absence of such to the MRA) or PHP and, incountries with no MRA they should also report to WHO through the disease control PHP.
6.6.8 The national public health and pharmacovigilance programmes The national pharmacovigilance centre will be responsible for the development ofpharmacovigilance in the public health system. The centre, jointly with the PHP, shoulddecide, on a continuous basis, priorities in pharmacovigilance for the PHP, whether all oronly a few priority medicines will be monitored, when to review adverse reactions, theduration of monitoring and the time frames for reporting and action, and should evaluatethe safety of the programme. The national pharmacovigilance centre will link with WHOfor technical and policy advice. It should also assist the national pharmacovigilancecoordinator in training activities. The centre will promote pharmacovigilance in the PHPsand sensitize professionals and public health staff to the reporting of adverse reactionsand irrational use of medicines.
The national coordinator should meet with the appropriate national PHP director toaddress issues relating to national and international need. The need for monitoringspecific medicines may arise when new programmes are begun, or when expanding thecoverage of a current programme. The beginning of a new programme could be a usefulstarting point for the development of a comprehensive national pharmacovigilance systemwith the support of all the above-mentioned players.
The media have an important role in creating awareness in the community and amongprofessionals. The Erice declaration (Annex 4) urges all players, including the media, tostrive towards the highest ethical, professional, and scientific standards in promoting thesafe use of medicines. WHO has made considerable efforts to train medicine regulatorsand national immunization staff in communicating information to the media on adverseevents following immunization.
It is important that the media are involved from the start of a PHP and that the need forthe programme is publicized together with the need for pharmacovigilance. Thepharmacovigilance programme should be explained and good lines of communicationshould be set up between the media and the ESRP or the designated liaison person, toensure the availability of authoritative information. The need for good information shouldbe anticipated so that potential crises can be dealt with quickly and effectively, and publicconfidence maintained.
It is desirable that one person, who can speak with authority and who is widely respected,is designated to be responsible for liaison with the media. This person should be 44 Integration of Pharmacovigilance into Public Health Programmes
appointed and trained in media relations before the programme begins. Professionalorganizations and health workers should be advised of appropriate procedures to followwhen faced with public concerns or questions from the media. The procedure shouldgenerally be to refer them to the media liaison person. This approach should limit thepossibility of conflicting messages coming from different sources. When communicatingwith the media, the following information should be available:— 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 anisolated occurrence, to prevent concern that it may be widespread.
— The likelihood that there will be new cases linked to therapy with the medicine.
— An outline of actions taken or planned (depending on the stage, this will range from a plan of action to a completed investigation).
— The cause of the event (when identified with reasonable certainty).
— The corrective action that has been or will be taken.
— 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 andattitudes as this will assist the development of future communication strategies.
6.6.10 The roles of WHO and the International Advisory Committee At an international level WHO will play a key role. While supporting countries toconduct PHPs, WHO and its regional offices have a responsibility to promote theestablishment and building of sustainable safety monitoring systems. WHO will take alead role in supporting Member States in the safe use of medicinal products. WHO willserve as a repository for information from both pharmacovigilance programmes andPHPs, and will disseminate this information appropriately. WHO will identify areasrequiring research and encourage and support initiatives to conduct operational research.
It will assist countries to define and develop policy on monitoring the safe use ofmedicinal products and it will respond to controversial issues on the safety of medicinesthat threaten the use of medicines in a national or international PHP. It will promote andencourage uniformity of terminology and will promote and develop resource materialsand 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:— are important to national or international programmes and have the potential to affect them adversely if not resolved; — cannot be met by structures and/or institutions and/or systems that are already — 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 anappropriate period of time, taking into account any existing information and theurgency of the issue; and/or — are likely to have policy implications for countries and which should meet policy needs including policy needs throughout WHO (the latter includes the conduct of andfuture developments in pharmacovigilance in all programmes throughout WHO); and Integration of Pharmacovigilance into Public Health Programmes 45
— will advance and promote the future development of pharmacovigilance as a 6.7 Where there is no national pharmacovigilance system
The development of pharmacovigilance within a PHP should be seen as animportant opportunity for the development of a comprehensive nationalpharmacovigilance system and should be seen as an obligatory investment in thefuture public health of the territory. In the absence of a national pharmacovigilance system, the development ofpharmacovigilance within a PHP should be seen as an important opportunity for thedevelopment of a comprehensive national pharmacovigilance system with the support ofthe experts involved. Indeed, this should be seen as an obligatory investment in the futurepublic health of the territory. It can be achieved by consultation and collaboration with:— the national MRA or ministry of health;— WHO headquarters, Geneva; and— WHO Collaborating Centre for International Drug Monitoring (Uppsala Monitoring Centre), Uppsala, Sweden.
The establishment of a national system for the safety of medicines, including a nationalpharmacovigilance centre, will facilitate pharmacovigilance within the PHP and enablepharmacovigilance to be coordinated between different PHPs, which will improveefficiency. The effect of this should be the availability of greater expertise in monitoringfor safety and a more cost-effective PHP.
Guidelines on setting up and running a pharmacovigilance centre have been published(3). It might be advantageous to establish the centre in a tertiary care hospital or anacademic institution (medical or pharmacy school).
6.8 Training and capacity building
Public health staff will not have received the training or have the expertisenecessary to deal with serious medicine-induced disease, unexpected adversereactions, adverse reactions to new medicines or adverse reactions in vulnerablegroups such as pregnant women, the very young or the very old. Training and capacity building in pharmacovigilance are required for staff working atperipheral health facilities because adverse reactions are not well understood and, inmany countries are seldom detected and reported. Monitoring is often neglected orabsent, and staff therefore need to be made aware that ADR monitoring is a part of goodprofessional practice. The identification of ADRs, the completion of reporting forms andprocedures for patient referral all need to be taught. Clinical teaching in the diagnosis ofadverse reactions is essential. Competence will need to be achieved in assistinginvestigations by the district investigation team. Motivation to continue monitoring over alonger period of time may diminish and the pharmacovigilance system may require theintroduction of training to sustain activities. Common concerns and barriers to reportingby health care personnel will need to be addressed during such training activities.
Communication issues also need to be addressed in training courses.
46 Integration of Pharmacovigilance into Public Health Programmes
It is recognized that countries need to develop and tailor their own national trainingmaterials to ensure relevance. Materials are best developed with the collaboration of theend-user to encourage ownership and facilitate the process of updating. Steps in thedevelopment of training materials include: assessment of needs, preparation of the firstdraft, revision, pilot-testing, finalization, printing, distribution, implementation, evaluationand updating. Staff in peripheral health facilities in rural and remote areas should beincluded in training schemes. These health workers have to deal with a high burden ofdisease, but receive minimal supervision.
In most disease-endemic countries, public health-care providers and professionals havenow been exposed to modern concepts of disease management. Most of those who haveused standard medicines are familiar with some of the common medicine-relatedproblems such as nausea following treatment with chloroquine.
Public health staff may have been made aware of vaccine-related adverse events andsystems for reporting them. However none of them will have the training and expertise todeal with serious medicine-induced disease, unexpected adverse reactions, adversereactions to new medicines, or adverse reactions in vulnerable groups such as pregnantwomen, the very young and the very old.
Training and capacity building of staff will be needed to help them carry out their dutiesagainst the changing scenario of greater use of medicines, wider coverage ofprogrammes, use of new medicines and the prophylactic use of medicines. Training forthese special needs can be integrated with the training for other programme-relatedactivities and will help reinforce this training.
Training and capacity building are required to ensure that staff understand newprescribing practices for new medicines, the correct dosage regimens and how treatmentfailures are defined. In conjunction, they need to be taught the reaction profile of themedicines they are to use, how to identify ADRs, how to manage them, when to referpatients, the basic data elements required in an ADR report, how to report, to whom andwhen. Clinical guidance for improving the recognition of serious adverse reactions isrequired. Staff will need to feel confident in reporting and assisting in the reviewingprocess. The ESRPs, the national pharmacovigilance coordinator and district healthofficer/programme manager should all be focal points in training programmes.
Timing of training is all-important. Training, distribution of treatment guidelines andquality reference materials for monitoring ADRs should precede the distribution of newmedicine, but only by a short time. Long delays between training and deployment of anew medicine cause confusion and frustration. Refresher courses, reinforcement throughnewsletters, posters and publications in local medical journals are good ways of ensuringthat the message is assimilated and can be recalled when required. Certification oftraining of personnnel employed in retail outlets would facilitate compliance withprescribing guidelines.
The national pharmacovigilance centre could give general training in pharmacovigilance.
Pharmacovigilance training for a specific programme should involve bothpharmacovigilance and public health staff. The pharmacovigilance training material couldbecome part of the programme manual.
Integration of Pharmacovigilance into Public Health Programmes 47
Capacity building of pharmacovigilance centre staff and the national pharmacovigilancecoordinator would be required to set up the pharmacovigilance component of a publichealth system, develop a reporting form and database, and enable analysis of adversereaction data and decision-making.
Training in communication skills is vital. The pharmacovigilance programme involvescommunication with the public and patients about the risks involved in using medicinesand the need to report any adverse experiences that are treatment-related. Explaining tothe media and elected government representatives the details of the pharmacovigilancesystem will build public confidence. Training in the preparation of a media statement onadverse reactions that have become headline news is essential so that a balanced andwell-reviewed report that justifies any action taken can be presented.
Motivation to continue monitoring may diminish over time and methods need to bedeveloped for sustaining a reporting culture. Common concerns and barriers to reportingby health care personnel will need to be addressed during training (e.g. fear of blame).
Training should be given to the entire team involved in the initial identification,investigation, management and reporting. Training and update programmes shouldinvolve the experts who are members of the ESRP.
6.9 Evaluation of the system
Evaluation and assessment should be built into the monitoring system. This willassist in achieving the goals of the programme. 6.9.1 Assessment of the pharmacovigilance system Evaluation and assessment should be built into the monitoring system. The nationalpharmacovigilance centre, coordinator and review panel should periodically evaluatewhether, or to what extent:— the reporting is complete, timely and accurate;— response has been swift enough;— case management has been appropriate; and— action has been appropriate to avoid programme error.
Ideally, a set of criteria should be identified by which the performance of thepharmacovigilance system may be evaluated. Such criteria may include:— distribution of reporting by professional category, specialization or patient reporting;— reporting quality, e.g. completeness of information, precision of description, contributory value to decision-making; — proportion of reports, describing reactions that are serious or previously unknown;— promptness of reporting;— reporting rate, e.g. the number of case reports per unit of population or number of health workers; and — evaluation of the impact of adverse reactions on morbidity, mortality and health care costs (often done by analysing hospital admissions due to ADRs).
48 Integration of Pharmacovigilance into Public Health Programmes
6.9.2 Impact of the pharmacovigilance system on the public health programme The pharmacovigilance system adopted may be comprehensive, or may be restricted to aspecific medicine or programme. It is envisaged that whatever system is used, it willundoubtedly help in the early detection and prompt management of adverse reactions, butwill also assist in achieving the goals of the programme. The pharmacovigilance traininggiven should result in a better understanding of the medicine being used in the PHP,better compliance by health workers with prescribing guidelines and better adherence ofpatients to dosing regimens, fewer drop-outs and the early detection of counterfeitmedicines. There is a need to conduct studies to evaluate the impact ofpharmacovigilance in public health, including comparative studies.
Integration of Pharmacovigilance into Public Health Programmes 49
Pharmacovigilance can strengthen dedicated national programmes such as thosefor the control and treatment of tuberculosis, malaria, HIV/AIDS, schistosomiasis,human African trypanosomiasis and immunization coverage. It is important that thetraditional division between medicine safety on the one hand and PHPs on theother should be removed. It is nearly 40 years since the World Health Assembly and WHO committed themselvesto developing the necessary scientific and clinical infrastructure to provide forsurveillance and monitoring of the safety of medicines in general use. Much has beenachieved since then. Pharmacovigilance, as the discipline has come to be known, issupported by the WHO Collaborating Centre for International Drug Monitoring, based in Uppsala, Sweden (the Uppsala Monitoring Centre), and a network of 78 countries thatare now affiliated as contributing centres. The MRAs have come to depend increasinglyon their national pharmacovigilance centres for the continuous review of the safety ofmedicines that they approve after licensing for general use, and for support of rationaluse of medicines — particularly those in use in the public sector.
Pharmacovigilance provides invaluable underpinning, or has the potential to do so, todedicated national programmes such as those for the control and treatment oftuberculosis, malaria, HIV/AIDS, schistosomiasis, human African trypanosomiasis andimmunization coverage. It is also essential in providing the necessary infrastructure foressential drugs programmes. Health ministries, health professionals and the public can allbe reassured by knowing that there is a competent and functional system in place thatfocuses on the safety of medicines used in the prevention and treatment of disease,including vaccines and pharmaceuticals for family planning. It is all the more importantthat there should be dependable monitoring of the safety of medicines as they becomeincreasingly potent and more widely available.
Experience has shown that for a country to be able to rely on its own pharmacovigilanceprogramme a number of elements need to be in place. These are as follows: — 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 theevaluation of reports of adverse events; — links, electronic and personal, between the pharmacovigilance centre and WHO, specifically with the Uppsala Monitoring Centre; — close operational ties with the national MRA that fulfil the mutual needs of the MRA and the pharmacovigilance centre for the evaluation and continuous monitoring of thesafety of medicines; — access to comprehensive and unbiased drug information relevant to the medicines available in the country; and, — a firm ethical underpinning of the operations of the pharmacovigilance programme as enshrined in the Erice Declaration (Annex 4).
50 Conclusions and Recommendations
Many of the 78 or so contributing national centres meet most of these requirements.
Currently, national centres are expected to respond to the special needs of programmes suchas national immunization programmes, HIV/AIDS programmes and introduction of newantimalarials and anti-tuberculosis drugs for treatment and prophylaxis. No MRA, howevercompetent and sophisticated it may be, can fully anticipate and meet the need to address thesafety and rational use of the new medicines prior to their introduction for general use.
It has been argued in this document that because medicines are central to PHPs, but have the potential to cause morbidity and even mortality through adverse effects, andaccepting the imperative that the use of medicines should be rational and cost-effective,pharmacovigilance is an indispensable public health activity. It is a crucial weakness inpharmacovigilance programmes that they are not fully integrated into national andregional PHPs and it does not make sense that the latter should function in isolation fromthe former. This report has explored the requirements for integrating the systems ofpharmacovigilance with national or regional PHPs. The benefits would be mutual, andconsiderable, in particular where resources are limited.
To achieve the objective of integrating pharmacovigilance with public health systems thefollowing are necessary. (What follows applies to countries with a minimum nationalpharmacovigilance system in place. Countries without such a national system will becovered later in this section.) — The national pharmacovigilance programme should have clinical underpinning, and should be known to and be actively supported by the ministry of health, healthprofessionals and the academic sector. The programme should have ready access tosound and independent drug information (particularly information on drug safety) andit should serve as a robust and dependable reference centre. The public should knowof 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 toperform these functions.
— 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. Whateverarrangement is made, there should be close collaboration, exchange of information,and mutual technical support between the centre and the MRA.
— A national medicines safety review committee (ESRP) for adverse reactions that advises both the MRA and the national pharmacovigilance centre, and that has strongclinical representation in its membership, should provide support and focus for thework of the national centre, and for the MRA.
— The scientific and clinical disciplines and methods that underpin PHPs — epidemiology, systematic review and outcomes measurement — are vital for thefuture successful operation of pharmacovigilance centres and for their integration intothe mainstream of public health. Outcomes analysis should be regarded as an inherentpart of the work of the national centre, so that its impact on the national diseaseprofile can be readily evaluated and demonstrated. The safe and rational use ofmedicines needs to be considered in conjunction with epidemiological profiles ofdisease if sound medicines policy is to be made.
— Pharmacovigilance centres, jointly with current PHPs, should address the special needs of the vulnerable regarding the safety of medicines (i.e. the very young, the Conclusions and Recommendations 51
elderly, pregnant women and patients with other diseases, e.g. renal, cardiac orhepatic disease), and of dedicated PHPs such as those for malaria, tuberculosis,HIV/AIDS, schistosomiasis, national immunization programmes and family planning.
For this purpose, they should have ready access to dedicated national andinternational databases in which safety reports on medicines are compiled andmanaged, and they should themselves be contributing to such information resources.
— Finally, there should be regular opportunities for the professional staff of pharmacovigilance centres to upgrade their knowledge and experience throughtraining, study and research — ideally in conjunction with colleagues in public health.
The World Health Organization has historically played a seminal and vital role inpromoting the safety of medicinal products as a clinical and public health issue. Thesuccess of WHO, in conjunction with the WHO Collaborating Centre for InternationalDrug Monitoring, in having established 78 national pharmacovigilance centres for thepurpose has been remarkable. In addition the signals that have been produced from thecentre have to a large extent led to changes in the labelling of medicines. An even greaterchallenge lies ahead — those countries that do not have the necessary facilities, expertiseand resources for pharmacovigilance arguably need them the most. In working to achievethis it will be important that the traditional division between medicine safety on the onehand and public health on the other should cease to exist. Technological advances ininformation capture, storage and retrieval, improved systems and resources for financingpublic health and medicine safety initiatives, specialization in medicine safety, and agrowing awareness of the importance to the public good of medicines that are safe andrationally used, in addition to their efficacy and good quality, should make theseobjectives realizable.
To explain how that might happen, and why, has been the purpose of this report.
52 Conclusions and Recommendations
1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalised patients: a meta-analysis of prospective studies. Journal of the AmericanMedical Association, 1998, 279:1200–1205.
2. Pirmohamed M, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. British Medical Journal, 2004, 329:15–19.
3. Safety monitoring of medicinal products — WHO Guidelines for setting up and running a pharmacovigilance centre. Stora Torget 3, Uppsala, Sweden, The UppsalaMonitoring Centre, 2000.
4. Potkar CN, Kshirsagar NA, Kathuria R. Resurgence of malaria and medicine resistance in Plasmodium falciparum and Plasmodium vivax species in Bombay.
Journal of Association of Physicians of India, 1995, 43:336–338.
5. Mengue SS, et al. Medicine use by pregnant women in six Brazilian cities. Revista de Saude Publica, 2001, 35:415–420.
6. Counterfeit medicines: guidelines for the development of measures to combat counterfeit medicines. Geneva, World Health Organization, 1999(WHO/EDM/QSM/99.1).
7. Csillag C. Epidemic of counterfeit drugs causes concern in Brazil. Lancet, 1998, 8. Singh J, et al. Diethylene glycol poisoning in Gurgaon India 1998. Bulletin of the World Health Organization, 2001, 79:88–95.
9. WHO Guidelines for Good Donation Practices Revised 1999. WHO/EDM/PAR/99.4.
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10. St John's Wort (Hypericum perforatum) interactions with medicines: EMEA, Canada, Malaysia, Netherlands, Sweden UK, USA . WHO Drug Alert 96, 3 March 2000.
11. Solomon AW, et al. Pilot study of the use of community volunteers to distribute azithromycin for trachoma control in Ghana. Bulletin of the World HealthOrganization, 2001, 79:6–14.
12. Report of the WHO Informal Consultation on the use of praziquantel during pregnancy/lactation. Geneva, World Health Organization, 2002(WHO/CDS/CPE/PVC/2002.4).
13. The importance of pharmacovigilance: safety monitoring of medicinal products.
Geneva, World Health Organization, 2002.
14. Effective communications in pharmacovigilance containing The Erice Declaration on communicating medicine safety information. Uppsala, Sweden, Uppsala MonitoringCentre, 1998.
15. Dialogue in pharmacovigilance — more effective communication. Uppsala, Sweden, Uppsala Monitoring Centre, 2002.
16. Surveillance of adverse events following immunization (AEFI) — Field guide for managers of immunization programmes (WHO/EPI/TRAM/93.02 Rev.1) 17. Mann R, Andrews E., eds. Pharmacovigilance. Chichester, Wiley & Sons, 2002.
18. Bénichou Ch. ed. Adverse drug reactions — a practical guide to diagnosis and management. Chichester, Wiley & Sons, 1994.
19. Council for International Organisations of Medical Sciences. Benefit-risk balance for marketed drugs: evaluating safety signals. Report of CIOMS Working Group IV.
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20. Shakir S. PEM in the UK and Coulter D. PEM in New Zealand. In: Mann R, Andrews E. eds. Pharmacovigilance. Chichester, Wiley & Sons, 2002, p. 333–362.

— to follow prescribed treatment and report adverse reactions to health-care provider Primary health-care worker — diagnose adverse reactions— manage adverse reactions— refer patients with serious and severe ADRs to district hospital for investigation andmanagement — make basic causality assessment— take action (stop medicine, stop use of batch, stop programme in area) if deemednecessary in consultation with DHO — send ADR reports to DHO— patient education— prevent programmatic errors— promote rational drug use— follow treatment guidelines— communicate with patients and public— attend meetings to receive feedback from Health-care provider outside — all of the above government system — may refer patient to primary health-care provider for further action District investigation team(a) District hospital — assess relationship/causality members: physician, nurse — investigate and manage ADRs, as advised by expert safety review committee — take action as advised by DHO— educate patients— be part of resource team for training primary health (b) DHO/district programme manager (as part of the — coordinate and complete the investigation of ADRs public health programme) — report the ADRs and follow-up details to the public health pharmacovigilance coordinator or the national pharmacovigilance coordinator — take interim action on continuation of the medicine — take action as advised by the expert safety review — training, supervision of primary and district level health-care teams — receives ADR reports from DIT — works under the national centre— coordinates the national pharmacovigilance — develops and adapts procedures; develops and maintains the national database for data processing,collection and storage of ADR records and signalgeneration; provides advice (especially if an 54 Summary of Roles and Responsibilities for Pharmacovigilance in Public Health Programmes
international agency is initiating the programme);maintains a supply of and distributes reporting forms — is a member/secretary for expert safety review panel; assists with assessment of case reports — develops training modules— liaises with public health, expert safety review panel, national centre, MRA, international agency — submits recommendations to public health, national pharmacovigilance centre, MRA Expert safety review panel — reviews ADRs, checks and finalizes causality assessments and possible signals — recommends additional investigations if needed— submits conclusions and recommendations to public health, national pharmacovigilance centre, MRA — provides resource person for training, education and — advises pharmacovigilance coordinator — supervises work of national coordinator — provides technical, training and managerial support for all pharmacovigilance activities — develops pharmacovigilance in the public health system and jointly decides on the specific goals forpharmacovigilance — serves as a resource for the MRA on a regular and — submits expert safety review panel recommendations with comments to public health and MRA — contributes to decision-making by MRA— liaises with UMC, WHO— liaises with sponsoring agency Public health programme — supervises work of DIT and programme manager— provides technical, training and managerial support for all functions of DIT and programme manager — takes programme-related decisions— liaises with national pharmacovigilance centre and decides jointly on the pharmacovigilance goals — receives reports from expert safety review panel and national pharmacovigilance centre — takes regulatory decisions— liaises with MRAs from other countries— liaises and consults with UMC and WHO WHO Collaborating Centre — provides guidance, technical support and training for International Drug for national pharmacovigilance centres or national Monitoring (Uppsala) — receives and processes ADR reports from national programmes or pharmacovigilance centres — provides regular feedback and specific services on WHO Headquarters, — provides the formal framework for collaboration in Geneva, Switzerland — provides funding and secretariat for the Advisory Committee on the Safety of Medicinal Products Summary of Roles and Responsibilities for Pharmacovigilance in Public Health Programmes 55
Advisory Committee on the — advances and promotes the future developments Safety of Medicinal of pharmacovigilance as a discipline — examines policy needs and their implications with respect to drug safety and pharmacovigilancefor WHO and countries — responds to identified needs of a country that may be beyond the capability of the country orcountries themselves; such responses should bemade within an appropriate timeframe, taking intoaccount any existing information and the urgencyof the issue; and/or — provides advice to national and international programmes when drug safety issues have thepotential to adversely affect them ADR, adverse drug reactions; DHO, district health officer; MRA, medicines regulatory authority; DIT, districtinvestigation team; UMC, Uppsala Monitoring Centre; WHO, World Health Organization.
56 Summary of Roles and Responsibilities for Pharmacovigilance in Public Health Programmes
There are several aspects of the experience gained with vaccines and their safetymonitoring that have relevance to pharmacovigilance in general.
It is as important for medicines as it is for vaccines to understand that adverse eventsmight arise from errors or deficiencies in transport or storage. Maintaining appropriateconditions for the preservation of the quality of the medicine is the equivalent ofmaintaining the cold chain for vaccines. Faulty dispensing or administration may alsooccur, e.g. as a result of dispensing from contaminated multi-dose vials. These potentialrisks with their consequent adverse effects are the equivalent of the "programmaticerrors" seen in vaccine programmes. An appreciation of the frequency of programmaticerrors is important.
The World Health Organization has developed, within the Department of Vaccines and Biologicals, and under the framework of the Global Training Network, a comprehensivetraining programme for the identification and reporting of adverse events following immunization. The training curriculum includes a component on communication to the public with a full explanation of safety issues that might be linked with vaccines.
Details of this training programme can be obtained from the department's web site(http://www.who.int/immunization_safety/en/) and in reports published in the WHO publi-cation, Weekly Epidemiological Records. At the time of writing this report (May 2004),more than 140 senior health professionals from 52 countries had been trained within thisprogramme. A network of vaccine safety experts within participating countries has beenestablished, and a number of individuals trained within the programme have subsequentlyserved as facilitators. It is anticipated that in this way a new leadership in the special issuesof vaccine pharmacovigilance will be established in the foreseeable future.
A further initiative of the Department of Vaccines and Biologicals at WHO that lends itselfto more general application in pharmacovigilance, was the establishment (in 1999) of aGlobal Advisory Committee for Vaccine Safety. This Committee, which includes experts in paediatrics, internal medicine, epidemiology and statistics, public health, virology and vaccinology, pharmacology and toxicology, provides independent and authoritative adviceto the director of the Department of Vaccines and Biologicals. The Committee allows nospecial advocacy considerations for vaccine programmes to influence its decisions regarding vaccine safety. The procedure of enquiry of the Advisory Committee is open, andall parties who might have an interest in the detail and the outcome of its deliberations areinvited to participate, and to make formal or informal representation. (This does not applyto the decision-taking of the Committee, which is confined, in camera to the members ofthe committee, to ensure its complete impartiality.) The Vaccine Safety Advisory Commit-tee has met twice yearly since 1999. The issues considered by the Committee are generallyof major potential national or international importance (real or perceived) that are likely tohave implications for immunization programmes and where, either proactively or reactivelyon the part of the advisory committee, the authority of WHO is sought for arbitration ofvaccine safety issues.
Vaccines Example 57
WHA18.42 Adverse Drug Reaction Monitoring System
The Eighteenth World Health Assembly
Handb. Res., 7th ed., Twelfth plenary meeting, 20 May 1965
(Committee on Programme and Budget, sixth report)
WHA19.35 International Monitoring of Adverse Reactions to Drugs
The Nineteenth World Health Assembly
Handb. Res., 8th ed., 1.3.3 Fourteenth plenary meeting, 20 May 1966
(Committee on Programme and Budget, fourth report)
WHA20.51 WHO Pilot Research Project for International Monitoring of Adverse
Reactions to Drugs
The Twentieth World Health Assembly
Handb. Res., 8th ed., 1.3.3 Twelfth plenary meeting, 25 May 1967
(Committee on Programme and Budget, ninth report)
WHA 23.13 International Monitoring of Adverse Reactions to Drugs
The Twenty-third World Health Assembly
Handb. Res., 10th ed., 1.10.1; Twelfth plenary meeting, 16 May 1970
(Committee A, first report)
58 World Health Assembly Resolutions
The following declaration was drawn up at the International Conference on DevelopingEffective Communications in Pharmacovigilance, Erice, Sicily, 24–27 September 1997. It was attended by health professionals, researchers, academics, media writers,representatives of the pharmaceutical industry, drug regulators, patients, lawyers,consumers and international health organizations. Monitoring, evaluating and communicating drug safety is a public-health activity withprofound implications that depend on the integrity and collective responsibility of allparties — consumers, health professionals, researchers, academia, media, pharmaceuticalindustry, drug regulators, governments and international organizations — workingtogether. High scientific, ethical and professional standards and a moral code shouldgovern this activity. The inherent uncertainty of the risks and benefits of drugs needs tobe acknowledged and explained. Decisions and actions that are based on this uncertaintyshould be informed by scientific and clinical considerations and should take into accountsocial realities and circumstances.
Flaws in drug safety communication at all levels of society can lead to mistrust,misinformation and misguided actions resulting in harm and the creation of a climatewhere drug safety data may be hidden, withheld, or ignored.
Fact should be distinguished from speculation and hypothesis, and actions taken shouldreflect the needs of those affected and the care they require. These actions call forsystems and legislation, nationally and internationally, that ensure full and open exchangeof information, and effective standards of evaluation. These standards will ensure thatrisks and benefits can be assessed, explained and acted upon openly and in a spirit thatpromotes general confidence and trust.
The following statements set forth the basic requirements for this to happen, and wereagreed upon by all participants from 34 countries at Erice: 1. Drug safety information must serve the health of the public. Such information should be ethically and effectively communicated in terms of both content andmethod. Facts, hypotheses and conclusions should be distinguished, uncertaintyacknowledged, and information provided in ways that meet both general andindividual needs.
2. Education in the appropriate use of drugs, including interpretation of safety information, is essential for the public at large, as well as for patients and healthcare providers. Such education requires special commitment and resources. Druginformation directed to the public in whatever form should be balanced with respectto risks and benefits.
Erice Declaration 59
3. All the evidence needed to assess and understand risks and benefits must be openly available. Constraints on communication parties, which hinder their ability to meetthis goal must be recognized and overcome.
4. Every country needs a system with independent expertise to ensure that safety information on all available drugs is adequately collected, impartially evaluated andmade accessible to all. Adequate nonpartisan financing must be available to supportthe system. Exchange of data and evaluations among countries must be encouragedand supported.
5. A strong basis for drug safety monitoring has been laid over a long period, although sometimes in response to disasters. Innovation in this field now needs to ensure thatemergent problems are promptly recognized and efficiently dealt with, and thatinformation and solutions are effectively communicated.
These ideals are achievable and the participants at the conference commit themselvesaccordingly. Details of what might be done to give effect to this declaration have beenconsidered at the conference and form the substance of the conference report.
Erice, 27 September 1997 The Conference was organized by: the Uppsala Monitoring Centre; the ClinicalPharmacology Unit, Institute of Pharmacology of Verona University; the Ettore MajoranaCentre for Scientific Culture, International School of Pharmacology; the World HealthOrganization and supported by EQUUS Communications, London.
60 Erice Declaration

Source: http://www.glpsolutions.it/pdf/normativa/bpf/linee%20guida/GPhVPWHO.pdf


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