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Methods 7: Pharmacovigilance: Voluntary Reporting and Opportunities for Active Surveillance
Invited commentator: Andy S Stergachis
Pilot Study of Cohort Event Monitoring (CEM) on Patients Treated for Malaria with Artemisinin Based Combination Therapies (ACTs) in Nigeria
1College of Medical Sciences University of Maiduguri, Nigeria; 2National Pharmacovigilance centre NAFDAC Abuja, FCT; 3Clinical Pharmacology Unit, University of Benin teaching hospital, Benin,Edo state; 4Department of Paediatrics Federal Medical Centre Gombe, Gombe State; 5Department of Paediatrics Ahmadu Bello University Teaching Hospital, Zaria Kaduna State; 6Department of Paediatrics Nnamdi Azikwe Teaching Hospital Enugu, Enugu State; 7Department of Obstetrics and Gynaecology, University College hospital Ibadan, Oyo State; 8University of Uyo Teaching Hospital, Akwa- Ibom State; 9NIPRD MOPD Clinic, Idishin Abuja – FCT; 10Quality Assurance and Safety of Medicines, WHO – Geneva, Switzerland.; 11Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring; 12Committee on safety of medicinal Products, WHO. New Zealand.
Problem statement: The emergence and spread of parasites resistant to available antimalarial drugs necessitated a shift in the malaria treatment policy by the federal government from the use of chloroquine and S-P as first-line treatment to the ACTs. Initial reports following deployment of the ACTs raised safety concerns regarding use in clinical settings. Moreover, the OTC classification of these medicines has made them readily available to Nigerians. Although, artemisinin and its derivatives are generally thought to be safe, there is currently little or no data on its safety among populations in Nigeria.
Objectives: The CEM provides a tool for proactively determining the adverse event (AE) profile of ACTs.
Study design: The study was observational, longitudinal, prospective, and inceptional whereby patients were observed under real life situations.
Setting: This CEM pilot was conducted across the 6 Nigerian public health facilities on patients who were treated for malaria with ACTs on the basis of 1 per geo-political zone. This provides a representation of cultural, ethnic, and religious diversity, which are strong considerations in Nigeria.
Study populations: A total of 3010 patients treated for malaria with ACTs were enrolled. All patients with a clinical diagnosis of malaria for whom artesunate amodiaquine (AA) or artemether-lumefantrine (AL) was prescribed were recruited, irrespective of age and sex. They were reviewed on days 3 and 7 following commencement of ACT treatment.
Outcome measure: Patients were evaluated for any clinical event/experience they had following the use of ACTs.
Results: The 5 common AEs seen in the two drugs AA/AL included general body weakness 388 (38%)/36 (4 %), dizziness 165 (16%)/16 (2%), vomiting 93 (9.0%)/11 (1.0%), abdominal pain 34 (3.4%)/11 (1.0%), and loss of appetite 39 (3.4%)/10 (1.0 %), respectively. The mean duration of events was 3 days. The events were more common in the AA group than the AL group. The study also shows that AL has a better safety profile than AA, however, both drugs demonstrate good clinical treatment outcome.
Conclusion: This pilot study suggests that AEs in ACTs are common, but that severe, life-threatening events are not. The mean duration of AEs is 3 days, after which clinical symptoms subsided in most subjects, suggesting that ACTs have a tolerable safety profile among Nigerians.
Funding sources: NAFDAC, WHO, NMCP, SFH, and YGC
Rapid Assessment Methods for Monitoring Pharmaceutical Policy
University of South Australia, Australia
Problem statement: The advent of computerised pharmaceutical dispensing data sets enables improved assessment of pharmaceutical policy; however, complex methodological designs can limit use. Methods that can be used by policy makers would facilitate improved monitoring of pharmaceutical policy.
Objectives: To provide a rapid assessment method for monitoring quality and safety of pharmaceutical use.
Design: We propose prescription sequence symmetry analysis as a potential method for rapid assessment of pharmaceutical use. The advantage of the method is its computational speed and its minimum data set requirement. Analyses can be undertaken within a day, and the method requires no more than three variables: drug name, date of supply, and a patient identifier. Sequence symmetry analysis examines asymmetry in the distribution of an incident event (e.g., either prescription of another medicine or hospitalisation) before and after the initiation of a specific treatment. Asymmetry may indicate an association of the specific medicine of interest with the event. The method uses a within-person design, making it robust towards confounders that are stable over time. A 12-month time window was used for safety assessments. Longer time windows were used for evaluating prior-use policies and quality-of-care indicators.
Setting: Australia, Taiwan, Japan, Korea, Sweden, USA
Results: A survey of countries participating in the Asian Pharmacoepidemiology Network (ASPEN) demonstrated the required variables are available in Japan, Korea, Taiwan, Sweden, the United States, and Australia. The method is amenable to a distributive network model in which analysis code is distributed to participants and results collated. A proof-of-concept study generated results from Japan, Taiwan, Australia, Korea, Sweden, and the United States. Pilot testing in Australia has shown the feasibility and practicality of the method. Prescription symmetry analysis of the risk of loop diuretics (indicative of heart failure treatment) after initiation of a nonsteroidal anti-inflammatory agents revealed an adjusted sequence rate ratio 1.3 (95% CI 1.20–1.41), which compared to a conventional cohort study of relative risk 1.33 (95% CI 1.10–1.60). Results also supported quality use of medicines assessments with prior-use assessment showing that only 57% of people had ever used atorvastatin prior to being initiated on the combination product, whereas only 46% had used tamoxifen prior to exemestane, despite the existence of a prior-use policy.
Conclusions: The use of sequence symmetry analyses provides timely and efficient evidence of safety issues associated with pharmaceuticals. Application using a distributive model overcomes problems of limited pharmacoepidemiological expertise. Modification of the design enables prior-use policies to be evaluated, whereas post-use assessment enables quality-of-care measures to be evaluated.
Funding source(s): Libby Roughead is supported by the Australian Research Council.
Challenges in Causality Assessment in Spontaneous Reporting Systems
Food and Drug Administration/CDER, United States of America
Regional and National Pharmacovigilance Centers
University of Ghana Medical School, Ghana
Role of the WHO Collaborating Centre for Advocacy and Training in Pharmacovigilance on the Establishment of National Centres in Africa
1University of Ghana Medical School, Accra, Ghana; 2World Health Organisation, Geneva, Switzerland; 3Uppsala Monitoring Centre, Uppsala, Sweden
Problem statement: Very few functional national pharmacovigilance (PV) centres exist in sub-Saharan Africa. This is due to several factors, including shortage of skilled personnel, financial limitations, weak health systems, and low priority for PV in the face of competing priorities. The need for PV systems in all countries is obvious however, especially in the current era in which access to medicines is improving as a result of huge donor inflows to support management of key diseases like HIV/AIDS, tuberculosis, and malaria and also to help in the attainment of the Millennium Development Goals.
Objectives: To examine the influence of a dedicated WHO Collaborating Centre on the establishment of national pharmacovigilance centres in sub-Saharan Africa
Method: In 2009, WHO designated the University of Ghana Medical School as a WHO Collaborating Centre for Advocacy and Research in Pharmacovigilance. The technical arm of the WHO PV programme, the Uppsala Monitoring Centre (UMC), also established an office in Accra (UMC-Africa) with both organisations having the prime objective of providing dedicated support for the establishment of pharmacovigilance centres in Africa. The main interventions undertaken were training and capacity building in pharmacovigilance, drug safety data management, and communication.
Results: A year after the establishment of the Collaborating Centre, the number of countries in sub-Saharan Africa with national PV centres participating as full members of the WHO Programme increased 40% from 15 to 21. Attainment of technical competence and full WHO PV Programme membership by 5 of these 6 countries was as an immediate and direct result of training and support by the WHO Collaborating Centre and UMC-Africa.
Discussion: Multinational organisations, donor agencies, and global normative bodies can stimulate the setting up of essential health systems and structures, such as national pharmacovigilance centres, by establishing regional centres to provide local support. Such regional centres, by their proximity to countries and understanding of regional problems, would be able to mobilise funds and provide long-term support to ensure sustainability of these centres. The need for earmarked funding for such regional coordinating centres is important to ensure that their activities are not stalled.
Conclusions: Focused interventions and regional support can yield remarkable results in the establishment of pharmacovigilance centres in resource-limited settings.
Funding sources: WHO