The Burden of Adverse Drug Reactions Due to Artemisinin-Based Antimalarial Treatment in Selected Ugandan Health Facilities: An Active Follow-Up Study.

INTRODUCTION: Uganda has rapidly increased access to antimalarial medicines in an effort to address the huge malaria disease burden. Pharmacovigilance information is important to guide policy decisions. OBJECTIVES: The purpose of this study was to establish the burden of adverse drug reactions (ADRs) and associated risk factors for developing ADRs to artemisinin-based antimalarial treatment in Uganda. METHODS: An active follow-up study was conducted between April and July 2017 in a cohort of patients receiving treatment for uncomplicated malaria in the Iganga, Mayuge, and Kampala districts. RESULTS: A total of 782 patients with a median age of 22 years (58.6% females) were recruited into this study, with the majority recruited from public health facilities (97%). Diagnostic tests before treatment were performed for 76% of patients, and 97% of patients received artemether/lumefantrine. The prevalence of ADRs was 22.5% (176/782); however, the total number of ADRs was 245 since some patients reported more than one ADR. The most commonly reported reactions were general body weakness (24%), headache (13%), and dizziness (11%). Women were more likely to develop an ADR (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.1-2.9), urban dwellers were more likely to develop an ADR than rural residents (aOR 9.9, 95% CI 5.4-17.9), and patients with comorbidities were more likely to develop an ADR than those without (aOR 7.4, 95% CI 4.4-12.3). CONCLUSION: The burden of ADRs is high among women and in patients from urban settings and those with comorbidities. Such risk factors need to be considered in order to optimise therapy. Close monitoring of ADRs is key in implementation of the malaria treatment policy

Expanding regulatory science: Regulatory complementarity and reliance

Abstract Drug regulatory institutions, infrastructures, and systems are becoming increasingly interconnected across national boundaries and increasingly global in outlook. This process is reflected in the broadening and deepening application of the principles and practice of Regulatory Reliance, and parallel initiatives to strengthen the capacities of regulatory institutions in low‐ and middle‐income countries (LMICs). Although these developments are important and constructive, they have tended to be framed in terms of the transfer of systems, knowledge, and skills from relatively “mature” regulatory agencies in high‐income countries (HICs) to less‐well‐resourced regulatory agencies in LMICs. This framing recognizes and foregrounds the considerable practical challenges that many LMIC regulatory agencies face, but in doing so, also backgrounds and underestimates the significance of the different contextual insights that LMIC health researchers and regulators can bring to the regulatory deliberations of their HIC counterparts. This position paper argues that the systematic pursuit, identification, and sharing of these different contextual insights—a dimension of regulatory science that we term “Regulatory Complementarity”—can augment the current practice and goals of Regulatory Reliance, and further invigorate the emerging global regulatory ecosystem

The effect of community dialogues and sensitization on patient reporting of adverse events in rural Uganda: Uncontrolled before-after study.

BackgroundPatients experiencing adverse drug events (ADE) in many developing countries are in the best position to report these events to the authorities but need to be empowered to do so. Systematic evaluation of community engagement and patient support especially in rural areas would provide evidence for a program to monitor potential harm from medicines. The aim of this study was to assess the effects of a community dialogue and sensitization (CDS) program on the knowledge, attitude and practises of community members for reporting ADE.MethodsThis an uncontrolled before-after study was conducted in two eastern Ugandan districts between September 2016 and August 2017.ResultsAfter implementation of the community dialogue and sensitization (CDS) program, there was an overall 20% (95% CI:16% to 25%) increase in knowledge about ADE in the community compared to before the program began. Awareness levels increased by 50% (95% CI: 37% to 63%) among those with little or no education and by41% (95% CI: 31% to 52%) among young people (15-24 years). Furthermore, 5% (95% CI: 3% to 7%) more respondents recognized the need for reporting ADEs compared to before the program. Finally, there was a significant increase of 115% (95% CI:137% to 217%) in respondent recognition and reporting of ADEs compared to the beginning of the CDS program. Overall, this community found the CDS program acceptable and proposed aspects that could be improved for future use.ConclusionOur evaluation showed that the CDS program increased knowledge and improved attitudes by catalyzing discussions among community members and healthcare professionals on health issues and monitoring safety of medicines compared to before the program. Successful implementation of the program depends on holistic health systems strengthening and adaptation to the community's way of life

Pharmacovigilance of suspected or confirmed therapeutic ineffectiveness of artemisinin-based combination therapy: extent, associated factors, challenges and solutions to reporting

Background: Therapeutic ineffectiveness of artemisinin-based combination therapy (ACT) increases the risk of malaria-related morbidity and mortality, and raises healthcare costs. Yet, little has been done to promote the pharmacovigilance (PV) of ACT ineffectiveness in sub-Saharan Africa, particularly in Uganda. This study aimed to determine the extent and associated factors of the past 6 months reporting of suspected or confirmed ACT therapeutic ineffectiveness by healthcare professionals (HCPs), and difficulties and potential solutions to the PV of ACT therapeutic ineffectiveness. Methods: Survey of 685 HCPs conducted using a self-administered questionnaire from June to July 2018 in a nationally representative sample of public and private health facilities in Uganda. HCPs disclosed if they had spontaneously reported ACT therapeutic ineffectiveness to appropriate authorities in the previous 6 months. Multivariable logistic regression models were used to identify determinants of past 6-months, HCP-reported ACT therapeutic ineffectiveness. Results: One in five (20%, 137/685; 95% CI 17-23%) HCPs reported ACT therapeutic ineffectiveness to an appropriate authority in the previous 6 months. HCPs commonly reported ACT therapeutic ineffectiveness to immediate supervisors (72%, 106/147), mostly verbally only (80%, 109/137); none had ever submitted a written report of ACT therapeutic ineffectiveness to Uganda's National Pharmacovigilance Centre. Common difficulties of reporting ACT therapeutic ineffectiveness were: unavailability of reporting procedures (31%, 129/421), poor follow-up of treated patients (22%, 93/421) and absence of reporting tools (16%, 68/421). Factors associated with reporting ACT therapeutic ineffectiveness in the past 6 months were: hospital-status (vs other; OR = 2.4, 95% CI 1.41-4.21), HCPs aged under 25 years (OR = 2.2, 95% CI 1.29-3.76), suspicion of ACT therapeutic ineffectiveness in the past 4 weeks (OR = 2.3, 95% CI 1.29-3.92), receipt of patient-complaint(s) of ACT therapeutic ineffectiveness in the past 4 weeks (OR = 2.9, 95% CI 1.62-5.12) and HCPs from northern (vs central; OR = 0.5, 95% CI 0.28-0.93) and western (vs central; OR = 0.4, 95% CI 0.17-0.77) parts of Uganda. Conclusion: One in five HCPs reported ACT therapeutic ineffectiveness, mostly verbally to supervisors. The existing adverse drug reaction (ADR)-reporting infrastructure could be leveraged to promote the PV of ACT therapeutic ineffectiveness

Pharmacovigilance of suspected or confirmed therapeutic ineffectiveness of artemisinin-based combination therapy: extent, associated factors, challenges and solutions to reporting

Background: Therapeutic ineffectiveness of artemisinin-based combination therapy (ACT) increases the risk of malaria-related morbidity and mortality, and raises healthcare costs. Yet, little has been done to promote the pharmacovigilance (PV) of ACT ineffectiveness in sub-Saharan Africa, particularly in Uganda. This study aimed to determine the extent and associated factors of the past 6 months reporting of suspected or confirmed ACT therapeutic ineffectiveness by healthcare professionals (HCPs), and difficulties and potential solutions to the PV of ACT therapeutic ineffectiveness. Methods: Survey of 685 HCPs conducted using a self-administered questionnaire from June to July 2018 in a nationally representative sample of public and private health facilities in Uganda. HCPs disclosed if they had spontaneously reported ACT therapeutic ineffectiveness to appropriate authorities in the previous 6 months. Multivariable logistic regression models were used to identify determinants of past 6-months, HCP-reported ACT therapeutic ineffectiveness. Results: One in five (20%, 137/685; 95% CI 17-23%) HCPs reported ACT therapeutic ineffectiveness to an appropriate authority in the previous 6 months. HCPs commonly reported ACT therapeutic ineffectiveness to immediate supervisors (72%, 106/147), mostly verbally only (80%, 109/137); none had ever submitted a written report of ACT therapeutic ineffectiveness to Uganda's National Pharmacovigilance Centre. Common difficulties of reporting ACT therapeutic ineffectiveness were: unavailability of reporting procedures (31%, 129/421), poor follow-up of treated patients (22%, 93/421) and absence of reporting tools (16%, 68/421). Factors associated with reporting ACT therapeutic ineffectiveness in the past 6 months were: hospital-status (vs other; OR = 2.4, 95% CI 1.41-4.21), HCPs aged under 25 years (OR = 2.2, 95% CI 1.29-3.76), suspicion of ACT therapeutic ineffectiveness in the past 4 weeks (OR = 2.3, 95% CI 1.29-3.92), receipt of patient-complaint(s) of ACT therapeutic ineffectiveness in the past 4 weeks (OR = 2.9, 95% CI 1.62-5.12) and HCPs from northern (vs central; OR = 0.5, 95% CI 0.28-0.93) and western (vs central; OR = 0.4, 95% CI 0.17-0.77) parts of Uganda. Conclusion: One in five HCPs reported ACT therapeutic ineffectiveness, mostly verbally to supervisors. The existing adverse drug reaction (ADR)-reporting infrastructure could be leveraged to promote the PV of ACT therapeutic ineffectiveness

The impact of the increase in import verification fees on local production capacity of selected medicines in Uganda

Abstract Background The local manufacture of pharmaceuticals is an opportunity to develop a broader manufacturing and knowledge-based economy and reduce over dependence on imports. To promote local production, the Ugandan government introduced Buy Uganda Build Uganda policy geared towards promoting use of locally manufactured goods. It also increased import verification fees in 2017 for 37 selected locally manufactured essential medicines from 2 to 12% to discourage importation of these medicines. This study assessed the impact of the increase in verification fees on local production capacity of the medicines. Methods This was a mixed methods study looking at production capacity before and after introduction of the 12% import verification fees. It was conducted among six (6) local pharmaceutical industries in Uganda and seven (7) key informant interviews with experts in the pharmaceutical sector between February and September 2021. Results The overall increase in local production capacity of the selected medicines was 8.2% from 2017 to 2020. The most significant increases were in the production of capsules (100.6%, P = 0.03) and oral liquids (170.8%, P = 0.0001). All the industries registered an increase in number of employees between 2017 and 2020 with an average percentage increase of 42%. There was a 14.7% (95% CI 2.76–17.6%) change in installed capacity of the compression machine (P = 0.033) and 27.7% (95% CI 24.6–33.9%) change in installed capacity of the Blow–Fill–Seal (BFS) filling machines (P = 0.011). There was also an increase in the number and capacity of installed utilities such as the heating ventilation and air conditioning (968%) and standby generators (131%). Only two (2) industries registered an increase in critical quality control equipment and one had all the critical equipment available by 2020. Most of the key informants reported positive impact of the increment of import verification on local manufacturing capacity. Conclusions Local pharmaceutical production capacity increased with the increase in import verification fees with significant increases in production of oral liquids and capsules. Successful implementation of policies supporting local production will promote the development of local pharmaceutical industries. Governments should consider increasing the list of medicines to benefit from the import verification fees increase by adding all essential generic medicines for which there is adequate domestic production capacity and technical skills

Healthcare professionals’ perspective can guide post-marketing surveillance of artemisinin-based combination therapy in Uganda

Background: Efficient testing to identify poor quality artemisinin-based combination therapy (ACT) is important to optimize efforts to control and eliminate malaria. Healthcare professionals interact with both ACT and malaria patients they treat and hence could observe, first-hand, suspect poor quality artemisinin-based combinations linked to poor malaria treatment outcomes and the factors associated with inappropriate use or treatment failure. Methods: A cross-sectional study of 685 HCP perspectives about the efficacy of ACT between June and July 2018 at selected health facilities in Uganda. Medicine samples were obtained from the seven regions of Uganda and tested for quality using the Germany Pharma Health Fund™ minilabs. Results: The average age of the 685 respondents was 30 (SD = 7.4) years. There was an almost equal distribution between male and female respondents (51:49), respectively. Seventy percent (n = 480) were diploma holders and the nurses contributed to half (49%, n = 334) of the study population. Sixty-one percent of the HCPs reported having ever encountered ACT failures while treating uncomplicated malaria. Nineteen percent of HCPs thought that dihydroartemisinin/piperaquine gave the most satisfactory patient treatment outcomes, while 80% HCPs thought that artemether/lumefantrine gave the least satisfactory patient treatment outcomes, possibly due to dosing schedule and pill burden. Healthcare professionals from the Central region (OR = 3.0, CI 0.3–1.0; P = 0.0001), Eastern region (OR = 5.4, CI 2.9–9.8; P = 0.0001) and Northern region (OR = 5.3, CI 2.9–9.9; P = 0.0001) had a higher chance of encountering ACT failure in 4 weeks prior to the survey as compared to those from the western region. Healthcare professionals from private health facilities also had higher chances of encountering ACT failures in past 4 weeks as compared to those from public health facilities (OR = 2.7, CI 1.7–3.9; P = 0.0001). All 192 samples passed the quality screening tests. The random sample of 10% of all samples randomly obtained by the laboratory staff also passed the chemical content analysis and dissolution tests. Conclusion: ACT medicines are widely available over-the-counter to the public and it is very difficult to report and monitor a decrease in efficacy or treatment failure. The perspectives of HCPs on treatment failure or lack of efficacy may potentially guide optimization efforts of sampling methodologies for the quality survey of ACT medicines

Effectiveness of the Med Safety mobile application in improving adverse drug reaction reporting by healthcare professionals in Uganda: a protocol for a pragmatic cluster-randomised controlled trial

INTRODUCTION: Combination antiretroviral therapy (cART) has massively reduced HIV mortality. However, long-term cART increases the risk of adverse drug reactions (ADRs), which can lead to higher morbidity, mortality and healthcare costs for people living with HIV (PLHIV). Pharmacovigilance—monitoring the effects of medicines—is essential for understanding real-world drug safety. In Uganda, pharmacovigilance systems have only recently been developed, and rates of ADR reporting for cART are very low. Thus, the safety profile of medicines currently used to treat HIV and tuberculosis in our population is poorly understood. The Med Safety mobile application has been developed through the European Union’s Innovative Medicines Initiative WEB-Recognising Adverse Drug Reactions project to promote digital pharmacovigilance. This mobile application has been approved for ADR-reporting by Uganda’s National Drug Authority. However, the barriers and facilitators to Med Safety uptake, and its effectiveness in improving pharmacovigilance, are as yet unknown. METHODS AND ANALYSIS: A pragmatic cluster-randomised controlled trial will be implemented over 30 months at 191 intervention and 191 comparison cART sites to evaluate Med Safety. Using a randomisation sequence generated by the sealed envelope software, we shall randomly assign the 382 prescreened cART sites to the intervention and comparison arms. Each cART site is a cluster that consists of healthcare professionals and PLHIV receiving dolutegravir-based cART and/or isoniazid preventive therapy. Healthcare professionals enrolled in the intervention arm will be trained in the use of mobile-based, paper-based and web-based reporting, while those in the comparison arm will be trained in paper-based and web-based reporting only. ETHICS AND DISSEMINATION: Ethical approval was given by the School of Biomedical Sciences Research and Ethics Committee at Makerere University (SBS-REC-720), and administrative clearance was obtained from Uganda National Council for Science and Technology (HS1366ES). Study results will be shared with healthcare professionals, policymakers, the public and academia. TRIAL REGISTRATION NUMBER: PACTR202009822379650