Pharmacovigilance Challenges in Community Pharmacy

Drug Safety

The use of medicines is an important aspect of many PHPs that are designed to improve the health of a target population. Their cost to the health budget is between 6% in developed countries and 45% in some developing countries, but there are huge variations between both developed countries and developing countries. Medicines are important not only because of their capacity to treat and prevent disease and to support PHPs, but also because the confidence of the public in the health policies of their countries is inextricably linked to their confidence in the availability of medicines that are safe and effective. All medicines carry some risk of harm and it is important to monitor their effects, both intended and unwanted, so that good evidence is available upon which to base an assessment of risk versus effectiveness or risk versus benefit. Furthermore, particularly with new medicines, the early identification of unexpected adverse reactions and their risk factors is essential, so that the medicines can be used in an informed manner with the least chance of harm. This is the role of pharmacovigilance. Information gathered during pharmacovigilance may also assist in selecting the most appropriate medicine for future use. Despite the progress that has been made in pharmacovigilance, the burden on public health of adverse reactions to medicines (traditionally referred to as ADRs) remains significant. Pharmacoeconomic studies on the costs of ADRs suggest that governments pay considerable amounts from their health budgets towards covering the costs associated with them. In a meta-analysis of 39 prospective studies from hospitals in the United States, 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 whole National Health Service bed base, suggests that for patients aged > 16 years, at any one time the equivalent of up to seven 800-bed hospitals may be occupied by patients admitted with ADRs. There are also costs associated with ADRs in primary health care, 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 sufficient data available to indicate that the provision of adequate strategies to detect and prevent adverse reactions is a cost- effective commitment of resources. Health requirements and the use of medicines in different countries vary considerably for many reasons, including different burdens of disease, economic, ethnic, cultural and dietary factors, and the level of development of a system for the regulation of medicines. Vigilance regarding both safety and effectiveness of medicines must become a priority area within public health. WHO has produced guidelines for setting up a national pharmacovigilance canter and many WHO PHPs have developed their own guidelines. The vaccines example is included in Annex 1. This document offers a critical examination of the strengths and weaknesses of both pharmacovigilance systems and public health systems. It describes the roles and responsibilities of all parties involved and anticipates the developments that will be necessary to enable both pharmacovigilance and PHPs to meet the challenges of the coming years. The increasing public expectation of safety is one of the major elements of the need for improving the safe use of medicinal products. As effective medicines become more widely available, there is an increasing demand for their use by the public and it is imperative that these medicines are monitored for safety. National pharmacovigilance centers cannot address this issue alone. They need to work together with other parties including the local regulatory authority, managers of PHPs, health professionals, academia, governments, the pharmaceutical industry, patients and consumers, and the media [2,3].

Public Health Programmes Using Medicines:

Public health is defined as the organized efforts of society to protect, promote and restore people health. The programs, services and institutions involved focus on the prevention of disease and the health needs of the population as a whole. Public health activities change in 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 [4]. Health promotion strategies contribute to the improvement of health and the prevention of diseases in developing and developed countries alike. Public health strategy is determined in each country according to the epidemiology of prevalent diseases and the local circumstances. Developing countries are facing a major challenge in tackling the communicable diseases that are responsible for high rates of morbidity and mortality. Infectious diseases for which effective treatment have existed for a long time, such as some diarrheal and respiratory diseases in children, continue to take their toll. Communicable diseases such as tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), sexually transmitted diseases (STDs), malaria, schistosomiasis, amoebiasis, leprosy, trachoma, lymphatic filariasis, intestinal helminthiasis, onchocerciasis, leishmaniosis and trypanosomiasis add to the disease burden [5]. Health authorities include in their basic health package PHPs aimed at reducing morbidity and mortality associated with the major common diseases. The important components of a PHP are education, environmental modifications, nutrition intervention, lifestyle and behavioral changes, preventive measures such as immunization, screening for hypertension and breast cancer and, in addition, pharmacotherapy [6]. The pharmaceutical industry is increasingly involved in either donating, or providing at reduced cost, medicines for direct administration to large populations and communities through a number of public health or disease control programs. Consumers and patients of affected communities are not usually involved directly in the decision-making process of the PHP. However, they influence the success of the desired outcome by accepting or rejecting the program. The success of PHPs depends on the active participation of the population and on multisectoral involvement [7].

The Public Health Environment:

Without good guidance and training programs for healthcare working   developing countries, patients could be at an increased risk of medication error and/or preventable ADRs.

Disease

Treatment is often initiated in the absence of an adequate diagnosis and there may be insufficient The diseases managed by the PHPs are not always well-diagnosed clinically. follow-up of patients. For example, because of inadequate diagnostic facilities, it is common clinical practice for patients to be given presumptive treatment for malaria although many of the patients treated will not have the disease [8].

Population

Public health programs may treat a large population over a short period. To meet the specific needs of a particular program, the community could be treated in one of three different ways: i.e. masse, case-contact or individual treatment. Under these conditions, some of the patients treated may not have the disease, or treatment could be given to patients in whom there are contraindications to the use of the medicine (e.g., pregnant, or breastfeeding women, young children or elderly people) [9].

Medicine

Huge quantities of medicines are used each year; for example, more than US$ 316 billion was 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 of medicines grew substantially between 1990 and 2000. In low-income countries such pharmaceuticals account for only about one third of total sales. Medicines can be generic with low commercial value (for example mebendazole), new medicines with which there is limited clinical experience (e.g, new antiretroviral) or still be undergoing clinical trials.

Health-care provider

In response to the increasing recognition of deficiencies in the provision of health care by existing health services, the concept of delivery of primary health-care by trained non- medical, village workers and involvement of the community has emerged. This has resulted in better implementation of national PHPs. However, there is frequently an inadequate understanding of adverse reactions even among highly trained personnel and more attention needs to be given to pharmacovigilance training in the curricula for medical and nursing undergraduates. This training in turn needs to be passed on to the non-medical health-care workers. The public health staffs responsible for the dispensing of medicines and the monitoring of responses are most often paramedics with educational levels that range from primary school to university graduate. Their training involves education in public health issues such as sanitation, nutrition, hygiene, family planning and on their role in the implementation of various programs. They lack training in the early detection and reporting of ADRs. When adverse events were reported at follow-up visits, the volunteers had difficulty in distinguishing patients with persistent or potentially more serious events from those in whom symptoms had abated or were abating [10].

Post Marketing surveillance

Pre-marketing study phase I, II, III trials necessary takes place in control situation selected groups of people. Though a new drug appears to be safe in this studies, unseen adverse effects can occur. When a drug is released for use in general population [11].

Public Health Programmes for Disease Control:

WHO plays an important role in the initiation, conduct and evaluation of PHPs and much effort is made to select, procure and distribute medicines, train staff and to educate the community to enlist their participation. [12,13] Decisions to start programs for public health are taken after considerable deliberation at the international and national levels. These PHPs are considered crucial for reducing mortality and morbidity. A significant part of the program budget is allocated to the procurement 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 procedures for implementation and monitoring of PHPs and much effort is made to select, procure and distribute medicines, train staff and to educate the community to enlist their participation. Detailed manuals are available on the practical procedures for the handling and use of the medicines or vaccines, particularly storage, administration, and contraindications. Each program has a standard therapeutic protocol following WHO technical guidance. Guidelines and training programs facilitate the proper conduct of thePHPs [14-16]. It is usual for a PHP to have a vertical organization and to be operated by a program manager. Program managers in charge of different programs do not necessarily collaborate. At the community level however, health professionals or community agents may be involved in several PHPs.

Pharmacovigilance:

Pharmacovigilance is the science and activity relating to the detection, assessment, understanding and prevention of adverse effects or any other possible medicine-related problem [17]. Some important definition requires to understand pharmacovigilance: -

Periodic Safety Update Reports (Psur)

The periodic safety update report for marketed drugs (PSUR) is intended to provide competent authorities with an update on periodic but comprehensive assessment of the worldwide safety data or biological product at defined times, post-authorization.

Pharmacoeconomics

Economic evaluation which is concerned with identifying, measuring and valuing inputs ti.e. estimating cost) and outputs (benefits) of a drug therapy or health care program as compared to alternative course of action or, if realistic, "doing nothing'. An assessment is made as to the collective improvement in the welfare of individuals relative to status quo, i.e. current normal practice [18].

Regulatory Authority

The legal authority in any country with the responsibility of regulating all matters relating to drugs. Examples: Drug Controller General of India (DCGI) for India, Food and Drug Administration (FDA) for USA, Medicines and Health care Products Regulatory Agency (MHRA) for UK. [19]

Effectiveness/Risk

The balance between the rate of effectiveness of medicine versus the risk or harm is a quantitative assessment of the merit of a medicine used in routine clinical practice. Comparative information between therapies is most useful. This is more useful than the efficacy and hazard predictions from pre-marketing information that is limited and based on selected subjects [20].

Drug

A drug or medicine is a pharmaceutical product, used in or on the human body for the prevention, diagnosis, or treatment of discase, or for the modification of physiological functions'

Data Safety Monitoring Board (Dsmb)

DSMB is used as a general term for a body that reviews interim trial data and which has the potential to influence the future conduct of a trial.

Development Safety Updatereport (Dsur)

As proposed by the COMS VIT Working Grip, DSUR is an internationally harmonized document modelled after the Periodic Safety Update Report PSUR) for marketed products. It is prepared by conducting an overall appraisal of safety din I regular intervals that allows recognition of rank, after thoughtful assessment and is approach communicated to all interested stakeholder, to support the safety of clinical trial subjects.

Epidemiology

The wince concerned with the study of the factor determining and influencing the frequency distribution of discase, injury and other health. plated events and their causes in a defined sum population for the purpose of establishing programs to prevent and control their development and spread (Dorland's Illustrated Medical Dictionary).

Origins of Pharmacovigilance

The history of pharmacovigilance goes back more than 40 years. In 1965 the eighteenth World Health Assembly, WHA 18.42, drew attention to the problem of adverse drug reaction monitoring and following further resolutions (see Annex 3) in 1966, 1967 and 1970 the International Drug Monitoring Program came into being. In 2005, 78 member countries are participating in this Program and the last decade has seen the participation of numerous developing countries. Pharmacovigilance Department of WHO, Geneva. Recently, the concerns of pharmacovigilance have been widened to include herbal, traditional and complementary medicines, blood products, biologicals, medical devices, and vaccines. Many other issues are also of relevance to the science of pharmacovigilance. These include substandard medicines, medication errors, lack of efficacy, use of medicines for indications that are not approved and for which there is inadequate scientific basis, case reports of acute and chronic poisoning, assessment of medicine-related mortality, abuse and misuse of medicines, and adverse interactions of medicines with chemicals, other medicines and foods and drinks. [21-22]

The cost advantages

A medicines monitoring system is an essential and cost-efficient means of detecting and minimizing injury to patients and averting potential disaster. Pharmacovigilance can help to better access and communicate information on the effectiveness and risks of medicines and to educate and inform patients. It is also an insurance against the undetected use of ineffective, substandard or counterfeit medicines, thus minimizing the possibility of wastage of resources. The cost of a pharmacovigilance system, compared with the cost of ADRs to a nation and to the total national expenditure on medicines, is small (see Introduction). The idea that pharmacovigilance is a luxury, affordable only in the developed world, should be replaced by the realization that a reliable system of pharmacovigilance is essential for the rational, safe and cost-effective use of medicines in all countries and consequently for public health, and should produce clear advantages in relation to cost. Pharmacovigilance has developed and will continue to develop in response to the special needs and according to the strengths of members of the WHO Pharmacovigilance Program. The ultimate benefit is the safe, rational, and effective use of medicines by patients. [23]

Effectiveness and Risk Assessment of Therapies:

Effectiveness and risk: benefit and harm:

Estimating the risk and benefit of medicines among the populations exposed to them is essential to promote their rational and safe use and will enhance the tolerability and acceptability of mass-treatment programs. The effectiveness and risk profiles of many of the medicines used in PHPs in the past have been established by long experience rather than based on epidemiological evidence. The modern approach to public health requires that advice be given on the best general ways of approaching the management of diseases, notwithstanding the necessity for considerable freedom to modify therapy according to individual needs. The Council for International Organizations of Medical Sciences has produced a monograph that gives much helpful practical advice on how to assemble information on 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 value judgements must be transparent. Nevertheless, the likely imbalance between the effectiveness data and risk data in terms of quantity, quality and the sources, remains a difficulty that is rarely addressed explicitly in comparative studies of therapies, whether pharmaceutical or other (such as surgery). Therefore, as medicine development progresses at a rapid pace, and WHO proactively, in partnership with industry, promotes the use of new medicines for the control of diseases in developing countries, there will be a paradigm shift in approach to ADR monitoring of medicines used in national programs. Estimating the risk and benefit of medicines for the populations exposed to them is essential to promote their rational and safe use and will enhance the acceptability and tolerability of mass- treatment programs. This estimation requires the monitoring of programs to detect, evaluate and prevent adverse reactions, including effects on pregnant women, the elderly and children. [24]

Crisis management in Pharmacovigilance:

Any event that comes to public notice and threatens the health or safety of individuals or groups, or the reputation or stability of an organization. Crises usually erupt suddenly and dramatically; they require rapid and effective response and communications. [25]

Management of a crisis requires not only resolution of the crisis event, but also very skilled management of the often-intense emotions and outrage that the public may feel. Any event that comes to public notice and threatens the health or safety of individuals or groups, or the reputation or stability of an organization. Crises usually erupt suddenly and dramatically; they require rapid and effective response and communications.

Pharmacovigilance and Public Health Programmes: Current Situation:

There can be better health outcomes as a consequence of good information on safety, which allows the early identification and prevention of adverse reactions, resulting in the more rational use of medicines, and better adherence within the target population.

1. Strengths:

Recently there have been some initiatives within countries, or under the leadership of WHO, to create and develop subsystems for pharmacovigilance to monitor the specific products used in their PHPs (e.g., vaccines, antiretroviral therapy, antimalarial programs and anthelminthic programs). On the other hand, some developing countries already have established pharmacovigilance centers that function independently. This situation provides all the ingredients for developing a unique and efficient pharmacovigilance system within PHPs and to integrate both systems. Although there are fundamental limitations and weaknesses in both PHPs and pharmacovigilance systems, PHPs have some distinct advantages for undertaking pharmacovigilance, and pharmacovigilance systems can benefit from the experience of PHPs.

2. Weaknesses

Although PHPs are well-established and are considered as crucial and essential for the health of any nation, pharmacovigilance often remains incorrectly perceived as a luxury. Discipline that governmental authorities cannot support and hence that only developed nations can afford. In most developing countries, there are insufficient resources within the public health system to undertake training and capacity building and to invest in systems for monitoring drug efficacy and safety. The major resources are often concentrated 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 and report adverse reactions to the medicines that are used in their programs and that have been on the market for a long time. In general, pharmacovigilance is not seen as a component of public health. The reasons for 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 a reporting culture. It is hoped that this document will encourage clinical program managers to develop a comprehensive understanding of the importance of pharmacovigilance. [26]

Integration of Pharmacovigilance   into Public Health Programmes:

Introduction

It is important to emphasize that the survival of a PHP may depend on good pharmacovigilance. The specific needs of countries and program managers in public health for their pharmacovigilance programs will differ as new initiatives are undertaken, and the efforts required will depend on the existing systems and infrastructure. It is important to emphasize that survival of a PHP may depend on good pharmacovigilance. Some countries have well-developed, functioning, national pharmacovigilance centers, which are backed by an MRA. In such countries there is also a strong public health department with separate staff dealing with each vertical disease-related program. In other countries, the public health department may employ the same staff to handle different disease programs and pharmacovigilance centers may be rudimentary or absent. National pharmacovigilance centers may be centralized or decentralized. In different countries 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 to be implementable not only in countries with pre-existing public health and pharmacovigilance systems, but also in countries with weak or deficient public health and pharmacovigilance programs. The model should emphasize sharing of human resources and the expansion of knowledge on effectiveness/risk, collaboration, effective communication, integration, training and capacity building. [27]