Pharmacovigilance in developing countries (part II): a path forward

In recent years, attention to pharmacovigilance has gained momentum in developing countries, however awareness of, and policies or systems for pharmacovigilance in most developing countries still lags sharply behind developed countries. This article proposes different strategies to encourage the introduction and sustain the advancement of robust pharmacovigilance systems in developing countries. To this end, this article seeks to accomplish the ultimate goal of pharmacovigilance in a developing country context; ensuring patient safety and promoting safe and rational use of drugs.     

Innovations for the future of pharmacovigilance.

Post-marketing pharmacovigilance involves the review and management of safety information from many sources. Among these sources, spontaneous adverse event reporting systems are among the most challenging and resource-intensive to manage. Traditionally, efforts to monitor spontaneous adverse event reporting systems have focused on review of individual case reports. The science of pharmacovigilance could be enhanced with the availability of systems-based tools that facilitate analysis of aggregate data for purposes of signal detection, signal evaluation and knowledge management. GlaxoSmithKline (GSK) recently implemented Online Signal Management (OSM) as a data-driven framework for managing the pharmacovigilance of marketed products. This pioneering work builds upon the strong history GSK has of innovation in this area. OSM is a software application co-developed by GSK and Lincoln Technologies that integrates traditional pharmacovigilance methods with modern quantitative statistical methods and data visualisation tools. OSM enables the rapid identification of trends from the individual adverse event reports received by GSK. OSM also provides knowledge-management tools to ensure the successful tracking of emerging safety issues. GSK has developed standard procedures and 'best practices' around the use of OSM to ensure the systematic evaluation of complex safety datasets. In summary, the implementation of OSM provides new tools and efficient processes to advance the science of pharmacovigilance.     

Evolving paradigms in pharmacovigilance

All medicines have adverse effects as well as benefits. The aim of pharmacovigilance is to protect public health by monitoring medicines to identify and evaluate issues and ensure that the overall benefits outweigh the potential risks. The tools and processes used in pharmacovigilance are continually evolving. Increasingly sophisticated tools are being designed to evaluate safety data from clinical trials to enhance the likelihood of detecting safety signals ahead of product registration. Methods include integration of safety data throughout development, meta-analytical techniques, quantitative and qualitative methods for evaluation of adverse event data and graphical tools to explore laboratory and biometric data. Electronic data capture facilitates monitoring of ongoing studies so that it is possible to promptly identify potential issues and manage patient safety. In addition, GSK employs a number of proactive methods for post-marketing signal detection and knowledge management using state-of-the-art statistical and analytical tools. Using these tools, together with safety data collected through pharmacoepidemiologic studies, literature and spontaneous reporting, potential adverse drug reactions can be better identified in marketed products. In summary, the information outlined in this paper provides a valuable benchmark for risk management and pharmacovigilance in pharmaceutical development.     

Pharmacovigilance regulations in India: A Step forward

Robust regulatory arrangements provide the foundation for a national method of medicine safety, and for public confidence in medicines. This article focuses on the need to sharpen the regulatory requirements for pharmacovigilance in India. To be effective the remit of drug regulatory authorities needs to go further than the approval of new medicines, to encompass a wider range of issues related to the safety of medicines. In order to achieve their respective objectives pharmacovigilance programs and drug regulatory authorities must be mutually supporting. On one hand, pharmacovigilance programs need to maintain strong links with the drug regulatory authorities to ensure that the latter are well briefed on safety issues in everyday clinical practice, whether these issues are relevant to future regulatory action or concerns that emerge in the public domain. On the other, regulators need to understand the pivotal role that pharmacovigilance plays in ensuring the ongoing safety of medicinal products. Despite global focus on the Development Safety Update Report, Indian regulators are not yet insistent on real-time update of a drug’s cumulative safety profile. Hence, the present article concludes with a strong urge to postulate regulations that create a comprehensive medicine safety system through careful strategic planning that envelope all aspects of pharmacovigilance.     

江苏省药品生产企业药物警戒工作现状抽样调查研究

目的本文立足于药品不良反应监测工作向药物警戒过渡的发展阶段,调查分析江苏省药品生产企业药物警戒工作的现状,为提升药品生产企业药物警戒工作能力提供依据与建议。方法采用问卷调查法,选取江苏省内药品生产企业代表,对其在药物警戒体系、药品安全性监测、药品风险管理等方面的工作现状进行调查,运用SPSS 22.0软件进行数据录入和统计。结果问卷调查覆盖各种类型药品生产企业共计108家,调查结果显示,大部分药品生产企业已初步建立药物警戒体系,在药品安全性监测方面的投入与成效日渐增加,但在药品风险管理方面相对薄弱。结论建议企业从提高重视程度、加强药物警戒体系建设、提升重点及薄弱环节工作有效性等方面加以完善,并建议监管部门及监测机构及时做好指南及培训相关配套。     

CIOMS and ICH initiatives in pharmacovigilance and risk management: overview and implications.

In this article we review the current initiatives by the Council for International Organizations of Medical Sciences (CIOMS) and the International Conference on Harmonisation (ICH) on pharmacovigilance planning that are due for general release during 2004. These initiatives could form the basis for applying concepts of risk management to medicines throughout their life cycle, from preclinical and clinical development to marketed use.The CIOMS VI Working Group (with 28 senior scientists worldwide from drug regulatory authorities and pharmaceutical companies) is currently developing scientific guidance that relates to clinical trials for medicines during development. It recommends a developmental pharmacovigilance concept - a 'living' concept that would start early in drug development supporting the science and ethics of research leading up to licensing (marketing authorisation) and continuing to post-authorisation (postmarketing) pharmacovigilance.This approach is seen as complementary to current ICH initiatives called 'Pharmacovigilance Planning'. ICH will introduce two concepts in pharmacovigilance management of medicinal products: the 'Pharmacovigilance Specification' and the 'Pharmacovigilance Plan'. The 'Pharmacovigilance Specification' will summarise important knowns and unknowns about the medicine. It will include safety risks identified at the licensing stage, potential risks and any key missing information. These elements will be essential to the formulation of pharmacovigilance plans.Dialogue and common understanding between regulators and the pharmaceutical industry will be a key factor for developing pharmacovigilance plans during the life cycle of medicines. Appropriate interaction with health professionals and patients should also be planned for the future as regulatory systems become more transparent.Where no significant issues are apparent at the licensing (marketing authorisation) stage, routine pharmacovigilance practices will be followed during the marketing phase. Where issues do exist or the data are limited, further study, including epidemiological approaches can be planned. All types of medicines (new drugs, biological agents, orphan drugs) may be involved in these concepts, as would major extensions to existing medicines.Currently ongoing CIOMS and ICH initiatives are in line with emerging risk-management strategies in the US, the European Union and Japan aimed at early and proactive pharmacovigilance.     

A call for international harmonization in therapeutic risk management

Therapeutic risk management is required to ensure that the benefits of a particular drug outweigh the risks in general practice. Current risk management strategies and handling of risk management and pharmacovigilance issues differ across borders. Differences in key regulatory decisions on the same product around the world, including the handling of safety issues with cisapride, dofetilide, and isotretinoin, bring into question the robustness of these decisions and the procedures currently in place to manage the risks to the public of products with potentially unfavorable risk-benefit balances. These differences may be partly due to differences in health care systems, regulatory requirements and procedures, and cultures. Greater international harmonization in approaches to risk management potentially would improve safety of medicines around the world by developing a greater uniformity in acquiring and interpreting risk-benefit evidence. The appropriateness and effectiveness of risk management interventions in different regions should be examined, and international strategies should be 'fine-tuned' for each regional health care setting. Recently issued international guidance on risk management and pharmacovigilance may help to improve consistency of decision-making around the world and promote better international communication and collaboration.     

From the Uppsala monitoring centre: a review of viewpoint part 1 and part 2.

The core task of the Uppsala Monitoring Centre (UMC) is the collection and processing of adverse drug reaction reports from member countries of the WHO Programme for International Drug Monitoring to detect early signals of potential drug hazards. Also a high priority is the communication of information about drug safety issues to the widest possible professional and general audiences in order to improve patient safety and welfare. The publication of the two parts of the publication Viewpoint represents a pioneering effort to provide easily accessible information on international pharmacovigilance for lay and specialist readers.     

What can consumer adverse drug reaction reporting add to existing health professional-based systems? Focus on the developing world.

The current system of pharmacovigilance encourages reporting of adverse drug reactions (ADRs) mainly from healthcare professionals. Underreporting is a major problem, more so in the developing world than in the developed world. Less than 3% of reports added to the WHO database in the year 2000 originated from developing countries, although around 80% of the global population lives in the developing world [corrected]. Also a considerable time lag still exists in recognition of serious ADRs. Hence, there is a need for a different approach to pharmacovigilance. We present an overview of possible reasons for underreporting by healthcare professionals with particular emphasis on the developing world, and the potential benefits of encouraging consumer reporting. Only a few countries accept consumer reports. We suggest an independent consumer reporting system for hypothesis generation to complement the present health professional-based system. We also highlight the low priority given by multinational pharmaceutical companies to the developing countries regarding new safety information. The important questions are whether the resources available would be sufficiently robust to sustain such a system in the developing world, and whether it will be sufficiently robust and sensitive for the early detection of signals.     

Pharmacovigilance in a rare disease: example of the VIGIAPATH program in pulmonary arterial hypertension

Spontaneous reporting is the primary method used in pharmacovigilance (PV) to detect drug safety signal. Specific criteria used in pharmacovigilance to prove accountability of a drug are rarely present in rare disease. The low number of alerts also makes it challenging. The aim of this commentary is to raise awareness among pharmacists on issues and opportunities for pharmacovigilance in rare diseases, taking pulmonary arterial hypertension (PAH) as example, from which a subset of cases are drug-induced. It is demonstrated how a dedicated program named VIGIAPATH created to reinforce pharmacovigilance of drug-induced pulmonary arterial hypertension at a national level, led to increase self-reporting and confirm safety signals. Thanks to a specific program such as VIGIAPATH, pharmacists can play an important role in communication with clinicians, patients and regulatory agencies, facilitating the detection of potential safety signals at an early stage in rare disease.     

欧盟药物警戒体系建立运行与实施进展

目的 对欧盟药物警戒体系及其实施进展进行介绍,为完善我国药物警戒体系提供参考。方法 通过查阅国内外文献,运用文献研究法进行分析。结果 在欧盟药物警戒体系内,其法律法规文件完整规范,各相关方职责明确,程序简化合理,信息公开透明,可合理有效的保障药品整个生命周期的安全。结论 我国应借鉴欧盟药物警戒体系,提高我国药品安全监测能力。     

Pharmacogenetics and rational drug use around the world

The WHO embraces evidence-based medicine to formulate an essential medicines list (EML) considering disease prevalence, drug efficacy, drug safety and cost-effectiveness. The EML is used by developing countries to build a national formulary. As pharmacogenetics in developed countries evolves, the Pharmacogenetics for Every Nation Initiative (PGENI) convened with representatives from China, Mexico, Ghana and South Africa in August 2009 to evaluate the use of human pharmacogenetics to enhance global drug use policy. The diseases causing mortality, the lack of integration of pharmacovigilance at the national formulary level, the pharmacogenetics research agenda and pharmacogenetics clinician education did not differ greatly among the countries. While there are many unanswered questions, systematically incorporating pharmacogenetics at the national formulary level promises to improve global drug use.     

新药临床试验期间药物警戒和风险控制研究五:我国药物警戒和风险控制监管体系调研与结果分析

目的：对我国新药临床试验期间药物警戒和风险控制的关键问题与管理要素进行业内调研,探索加强该领域监管的可行措施。方法：在对欧美新药临床试验期间药物警戒体系,临床试验方案、研究者手册和知情同意书的监管要求,临床试验期间安全性定期报告监管要求以及药物临床试验期间个例安全性报告监管要求等文献研究的基础上,提炼关键管理要素,设计调研问卷,开展问卷调查,并对调查结果进行分析。采用非概率抽样法,选择从事与药物警戒相关工作的专业人员作为调研对象。结果与结论：调查结果反映出多数调研对象对我国新药临床试验期间药物警戒和风险控制的关键问题与管理要素有一定共识,本调研为进一步提出我国新药临床试验期间药物警戒和风险控制管理的完善建议提供了数据支持。     

对医疗机构开展药物警戒工作的认识与探讨

通过研究医疗机构药品使用与安全监管现状,分析药物警戒体系在药品使用环节对安全、有效、合理用药的重要作用,探索医疗机构开展药物警戒工作的内容与方法,建议制定相关法规,保障该项工作的开展。     

The WHO 'Roll Back Malaria Project': planning for adverse event monitoring in Africa.

Artemisinin combination therapies (ACTs) have been recommended for the treatment of malaria in countries where there is widespread resistance to commonly used antimalarial drugs. Several sub-Saharan African countries are, therefore, in the process of introducing ACTs in their malaria drug policies. However, there is limited information about the safety of ACTs outside South East Asia, where their use has been well documented. As with all other new medicinal compounds, the monitoring of a drug's safety or 'pharmacovigilance' is important, especially in areas where co-morbid conditions, such as HIV/AIDS, malnutrition and tuberculosis, are common. Because in most malaria endemic countries, particularly Africa, there are no pharmacovigilance programmes in place, it has been suggested that the introduction of ACTs offers an opportunity for these countries to put drug safety monitoring systems in place. Backed by the WHO Roll Back Malaria department and other international cooperating partners, five African countries, which are in the process of introducing ACTs (Burundi, Democratic Republic of the Congo, Mozambique, Zambia and Zanzibar), have drawn up action plans to introduce pharmacovigilance in their health sector. It is planned that once the safety monitoring of antimalarials has been established, these activities can then be extended to cover medicinal compounds used in other public health programmes, such as HIV/AIDS, tuberculosis and the immunisation programmes. This article looks at the rationale for pharmacovigilance, the process of setting up monitoring centres and the challenges of implementing the project in the region.     

Effective integration of pharmacovigilance systems at public health facilities in resource-limited settings: A qualitative study

BackgroundPharmacovigilance systems increase access to safe medicines and healthcare, but their integration in public healthcare remains a challenge in many countries. The main barriers to pharmacovigilance integration are attributed to high patient load and limited capacities.ObjectiveTo explore the challenges associated with the effective integration of pharmacovigilance systems in public healthcare in a developing country such as Namibia.MethodsA nationwide qualitative assessment of integration of pharmacovigilance systems particularly spontaneous adverse drug reaction (ADR) reporting at public health facility level was conducted. Key informant interviews were conducted among pivotal healthcare professionals involved in pharmacovigilance. The main outcomes were themes on challenges and strategies for effective integration of PV services at the facility level. Qualitative data were collected over a one-month period (i.e., March 2019), and thematically analysed.ResultsEight (8) key informants were recruited; the majority were pharmacists (n = 7) and male (n = 5). The main challenges affecting the effective integration of pharmacovigilance systems reporting at public health facilities were “weak pharmacovigilance policies and structures”, “negative attitude of healthcare workers towards pharmacovigilance”, and “limited capacity and support for implementation of pharmacovigilance activities”. The main strategies for effective integration of PV systems at facilities included local capacity-building through continuing profession education and support, advocacy, stakeholder engagement, facility/region based pharmacovigilance champions, and facility-based policies for universal and inclusive reporting, (i.e. patients and health workers at all levels) as well as development of workable standard operational procedures.ConclusionsThe pharmacovigilance systems at healthcare facilities in Namibia were observed to have sub-optimal policies, structures and support systems, and lack health care worker buy-in. There is a need for a policy framework to ensure effective and sustainable integration of pharmacovigilance activities at public healthcare facilities.     

Using MedDRA: implications for risk management.

The introduction of MedDRA, the Medical Dictionary for Regulatory Activities, as a standardised terminology may have a major impact on the performance of risk management. Thus, MedDRA is likely to have an important effect on the analysis of clinical trial safety data. Review of the most commonly used terms in clinical trial tables from the labelling of ten products indicated that each adverse event could be represented by many MedDRA preferred terms; this might theoretically lead to failure to identify differences in adverse event incidence between treatment arms. Possible solutions are proposed. The use of MedDRA in spontaneous reporting systems is a regulatory requirement in some countries. Variability in modes of implementation and use of the terminology are discussed; these may impose additional limitations on any use of spontaneous data for comparative purposes. There are important differences in the ways that safety databases interface with MedDRA and uncertainty about the most appropriate way to manage version changes. The characteristics of MedDRA must be taken into account when establishing methods for signal detection and its use will affect the retrieval of similar cases as required for signal evaluation. The use of MedDRA in the periodic safety update report is discussed. The possible use of MedDRA in pharmacoepidemiology is highly relevant to risk management, and some issues are briefly outlined. With regard to communication of risk, if MedDRA is introduced into existing product labelling, care must be taken that the change itself does not cause misunderstanding; the most appropriate use of MedDRA in this regard remains to be determined. There is a need for careful evaluation of MedDRA in fulfilling its various functions in pharmacovigilance, followed by definitive regulatory guidance on its use.     

Pharmacy students’ knowledge and perceptions about adverse drug reactions reporting and pharmacovigilance

Pharmacy students’ knowledge about adverse drug reaction reporting can impact their attitude towards patient care and issues on patient safety. The aim of this study was to investigate the knowledge and perception of pharmacy students about adverse drug reaction reporting and pharmacovigilance and to study their willingness to report. A cross-sectional study using a validated questionnaire was conducted among the university students. The demographic details of the respondents were studied. The number of female respondents was comparatively higher than the male respondents. There were no significant differences by gender regarding the knowledge on adverse drug reaction reporting and pharmacovigilance except with the knowledge of post-marketing surveillance for which male students appeared to be more knowledgeable than female students. The results showed that the pharmacy students had sufficient knowledge and there are significant differences in perception among the students on adverse drug reaction reporting.     

Using real-world healthcare data for pharmacovigilance signal detection – the experience of the EU-ADR project

A prospective pharmacovigilance signal detection study, comparing the real-world healthcare data (EU-ADR) and two spontaneous reporting system (SRS) databases, US FDA’s Adverse Event Reporting System and WHO's Vigibase is reported. The study compared drug safety signals found in the EU-ADR and SRS databases. The potential for signal detection in the EU-ADR system was found to be dependent on frequency of the event and utilization of drugs in the general population. The EU-ADR system may have a greater potential for detecting signals for events occurring at higher frequency in general population and those that are commonly not considered as potentially a drug-induced event. Factors influencing various differences between the datasets are discussed along with potential limitations and applications to pharmacovigilance practice.