Working towards consensus on methods used to elicit participant-reported safety data in uncomplicated malaria clinical drug studies: a Delphi technique study

BACKGROUND: Eliciting adverse event (AE) and non-study medication data reports from clinical research participants is integral to evaluating drug safety. However, using different methods to question participants yields inconsistent results, compromising the interpretation, comparison and pooling of data across studies. This is particularly important given the widespread use of anti-malarials in vulnerable populations, and their increasing use in healthy, but at-risk individuals, as preventive treatment or to reduce malaria transmission. METHODS: Experienced and knowledgeable anti-malarial drug clinical researchers were invited to participate in a Delphi technique study, to facilitate consensus on what are considered optimal (relevant, important and feasible) methods, tools, and approaches for detecting participant-reported AE and non-study medication data in uncomplicated malaria treatment studies. RESULTS: Of 72 invited, 25, 16 and 10 panellists responded to the first, second and third rounds of the Delphi, respectively. Overall, 68% (68/100) of all questioning items presented for rating achieved consensus. When asking general questions about health, panellists agreed on the utility of a question/concept about any change in health, taking care to ensure that such questions/concepts do not imply causality. Eighty-nine percent (39/44) of specific signs and symptoms questions were rated as optimal. For non-study medications, a general question and most structured questioning items were considered an optimal approach. The use of mobile phones, patient diaries, rating scales as well as openly engaging with participants to discuss concerns were also considered optimal complementary data-elicitation tools. CONCLUSIONS: This study succeeded in reaching consensus within a section of the anti-malarial drug clinical research community about using a general question concept, and structured questions for eliciting data about AEs and non-study medication reports. The concepts and items considered in this Delphi to be relevant, important and feasible should be further investigated for potential inclusion in a harmonized approach to collect participant-elicited anti-malarial drug safety data. This, in turn, should improve understanding of anti-malarial drug safety

Making morbidity multiple: History, legacies, and possibilities for global health

Multimorbidity has been framed as a pressing global health challenge that exposes the limits of systems organised around single diseases. This article seeks to expand and strengthen current thinking around multimorbidity by analysing its construction within the field of global health. We suggest that the significance of multimorbidity lies not only in challenging divisions between disease categories but also in what it reveals about the culture and history of transnational biomedicine. Drawing on social research from sub-Saharan Africa to ground our arguments, we begin by describing the historical processes through which morbidity was made divisible in biomedicine and how the single disease became integral not only to disease control but to the extension of biopolitical power. Multimorbidity, we observe, is hoped to challenge single disease approaches but is assembled from the same problematic, historically-loaded categories that it exposes as breaking down. Next, we highlight the consequences of such classificatory legacies in everyday lives and suggest why frameworks and interventions to integrate care have tended to have limited traction in practice. Finally, we argue that efforts to align priorities and disciplines around a standardised biomedical definition of multimorbidity risks retracing the same steps. We call for transdisciplinary work across the field of global health around a more holistic, reflexive understanding of multimorbidity that foregrounds the culture and history of translocated biomedicine, the intractability of single disease thinking, and its often-adverse consequences in local worlds. We outline key domains within the architecture of global health where transformation is needed, including care delivery, medical training, the organisation of knowledge and expertise, global governance, and financing

Understanding antimicrobial use in subsistence farmers in Chikwawa District Malawi, implications for public awareness campaigns

Drug resistant infections are increasing across the world and urgent action is required to preserve current classes of antibiotics. Antibiotic use practices in low-and-middle-income countries have gained international attention, especially as antibiotics are often accessed beyond the formal health system. Public awareness campaigns have gained popularity, often conceptualising antimicrobial resistance (AMR) as a problem of excess, precipitated by irrational behaviour. Insufficient attention has been paid to people’s lived experiences of accessing medicines in low-income contexts. In Chikwawa District, Malawi, a place of extreme scarcity, our study aimed to understand the care and medicine use practices of households dependent on subsistence farming. Adopting an anthropological approach, we undertook medicine interviews (100), ethnographic fieldwork (six-month period) and key informant interviews (33) with a range of participants in two villages in rural Chikwawa. The most frequently used drugs were cotrimoxazole and amoxicillin, not considered to be of critical importance to human health. Participants recognised that keeping, sharing, and buying medicines informally was not the “right thing.” However, they described using antibiotics and other medicines in these ways due to conditions of extreme precarity, the costs and limitations of seeking formal care in the public sector, and the inevitability of future illness. Our findings emphasise the need in contexts of extreme scarcity to equip policy actors with interventions to address AMR through strengthening health systems, rather than public awareness campaigns that foreground overuse and the dangers of using antibiotics beyond the formal sector

The impact of an intervention to introduce malaria rapid diagnostic tests on fever case management in a high transmission setting in Uganda: A mixed-methods cluster-randomized trial (PRIME).

Rapid diagnostic tests for malaria (mRDTs) have been scaled-up widely across Africa. The PRIME study evaluated an intervention aiming to improve fever case management using mRDTs at public health centers in Uganda. A cluster-randomized trial was conducted from 2010-13 in Tororo, a high malaria transmission setting. Twenty public health centers were randomized in a 1:1 ratio to intervention or control. The intervention included training in health center management, fever case management with mRDTs, and patient-centered services; plus provision of mRDTs and artemether-lumefantrine (AL) when stocks ran low. Three rounds of Interviews were conducted with caregivers of children under five years of age as they exited health centers (N = 1400); reference mRDTs were done in children with fever (N = 1336). Health worker perspectives on mRDTs were elicited through semi-structured questionnaires (N = 49) and in-depth interviews (N = 10). The primary outcome was inappropriate treatment of malaria, defined as the proportion of febrile children who were not treated according to guidelines based on the reference mRDT. There was no difference in inappropriate treatment of malaria between the intervention and control arms (24.0% versus 29.7%, adjusted risk ratio 0.81 95\% CI: 0.56, 1.17 p = 0.24). Most children (76.0\%) tested positive by reference mRDT, but many were not prescribed AL (22.5\% intervention versus 25.9\% control, p = 0.53). Inappropriate treatment of children testing negative by reference mRDT with AL was also common (31.3\% invention vs 42.4\% control, p = 0.29). Health workers appreciated mRDTs but felt that integrating testing into practice was challenging given constraints on time and infrastructure. The PRIME intervention did not have the desired impact on inappropriate treatment of malaria for children under five. In this high transmission setting, use of mRDTs did not lead to the reductions in antimalarial prescribing seen elsewhere. Broader investment in health systems, including infrastructure and staffing, will be required to improve fever case management

Basic or enhanced clinician training to improve adherence to malaria treatment guidelines: a cluster-randomised trial in two areas of Cameroon

Background The scale-up of malaria rapid diagnostic tests (RDTs) is intended to improve case management of fever and targeting of artemisinin-based combination therapy. Habitual presumptive treatment has hampered these intentions, suggesting a need for strategies to support behaviour change. We aimed to assess the introduction of RDTs when packaged with basic or enhanced clinician training interventions in Cameroon. Methods We did a three-arm, stratifi ed, cluster-randomised trial at 46 public and mission health facilities at two study sites in Cameroon to compare three approaches to malaria diagnosis. Facilities were randomly assigned by a computer program in a 9:19:19 ratio to current practice with microscopy (widely available, used as a control group); RDTs with a basic (1 day) clinician training intervention; or RDTs with an enhanced (3 days) clinician training intervention. Patients (or their carers) and fi eldworkers who administered surveys to obtain outcome data were masked to study group assignment. The primary outcome was the proportion of patients treated in accordance with WHO malaria treatment guidelines, which is a composite indicator of whether patients were tested for malaria and given appropriate treatment consistent with the test result. All analyses were by intention to treat. This study is registered at ClinicalTrials. gov, number NCT01350752. Findings The study took place between June 7 and Dec 14, 2011. The analysis included 681 patients from nine facilities in the control group, 1632 patients from 18 facilities in the basic-training group, and 1669 from 19 facilities in the enhanced-training group. The proportion of patients treated in accordance with malaria guidelines did not improve with either intervention; the adjusted risk ratio (RR) for basic training compared with control was 1·04 (95% CI 0·53–2·07; p=0·90), and for enhanced training compared with control was 1·17 (0·61–2·25; p=0·62). Inappropriate use of antimalarial drugs after a negative test was reduced from 84% (201/239) in the control group to 52% (413/796) in the basic-training group (unadjusted RR 0·63, 0·28–1·43; p=0·25) and to 31% (232/759) in the enhanced-training group (0·29, 0·11–0·77; p=0·02). Interpretation Enhanced clinician training, designed to translate knowledge into prescribing practice and improve quality of care, has the potential to halve overtreatment in public and mission health facilities in Cameroon. Basic training is unlikely to be suffi cient to support the behaviour change required for the introduction of RDTs

Antibiotic stories:A mixed-methods, multi-country analysis of household antibiotic use in Malawi, Uganda and Zimbabwe

Background As concerns about the prevalence of infections that are resistant to available antibiotics increase, attention has turned toward the use of these medicines both within and outside of formal healthcare settings. Much of what is known about use beyond formal settings is informed by survey-based research. Few studies to date have used comparative, mixed-methods approaches to render visible patterns of use within and between settings as well as wider points of context shaping these patterns. Design This article analyses findings from mixed-methods anthropological studies of antibiotic use in a range of rural and urban settings in Zimbabwe, Malawi and Uganda between 2018 and 2020. All used a ‘drug bag’ survey tool to capture the frequency and types of antibiotics used among 1811 households. We then undertook observations and interviews in residential settings, with health providers and key stakeholders to better understand the stories behind the most-used antibiotics. Results The most self-reported ‘frequently used’ antibiotics across settings were amoxicillin, cotrimoxazole and metronidazole. The stories behind their use varied between settings, reflecting differences in the configuration of health systems and antibiotic supplies. At the same time, these stories reveal cross-cutting features and omissions of contemporary global health programming that shape the contours of antibiotic (over)use at national and local levels. Conclusions Our findings challenge the predominant focus of stewardship frameworks on the practices of antibiotic end users. We suggest future interventions could consider systems—rather than individuals—as stewards of antibiotics, reducing the need to rely on these medicines to fix other issues of inequity, productivity and security

Strengthening patient-centred communication in rural Ugandan health centres: A theory-driven evaluation within a cluster randomized trial.

This article describes a theory-driven evaluation of one component of an intervention to improve the quality of health care at Ugandan public health centres. Patient-centred services have been advocated widely, but such approaches have received little attention in Africa. A cluster randomized trial is evaluating population-level outcomes of an intervention with multiple components, including 'patient-centred services.' A process evaluation was designed within this trial to articulate and evaluate the implementation and programme theories of the intervention. This article evaluates one hypothesized mechanism of change within the programme theory: the impact of the Patient Centred Services component on health-worker communication. The theory-driven approach extended to evaluation of the outcome measures. The study found that the proximal outcome of patient-centred communication was rated 10 percent higher (p < 0.008) by care seekers consulting with the health workers who were at the intervention health centres compared with those at control health centres. This finding will strengthen interpretation of more distal trial outcomes

A Cluster Randomised Trial Introducing Rapid Diagnostic Tests into Registered Drug Shops in Uganda: Impact on Appropriate Treatment of Malaria

Background: Inappropriate treatment of malaria is widely reported particularly in areas where there is poor access to health facilities and self-treatment of fevers with anti-malarial drugs bought in shops is the most common form of care-seeking. The main objective of the study was to examine the impact of introducing rapid diagnostic tests for malaria (mRDTs) in registered drug shops in Uganda, with the aim to increase appropriate treatment of malaria with artemisinin-based combination therapy (ACT) in patients seeking treatment for fever in drug shops. Methods: A cluster-randomized trial of introducing mRDTs in registered drug shops was implemented in 20 geographical clusters of drug shops in Mukono district, central Uganda. Ten clusters were randomly allocated to the intervention (diagnostic confirmation of malaria by mRDT followed by ACT) and ten clusters to the control arm (presumptive treatment of fevers with ACT). Treatment decisions by providers were validated by microscopy on a reference blood slide collected at the time of consultation. The primary outcome was the proportion of febrile patients receiving appropriate treatment with ACT defined as: malaria patients with microscopically-confirmed presence of parasites in a peripheral blood smear receiving ACT or rectal artesunate, and patients with no malaria parasites not given ACT. Findings: A total of 15,517 eligible patients (8672 intervention and 6845 control) received treatment for fever between January-December 2011. The proportion of febrile patients who received appropriate ACT treatment was 72·9% versus 33·7% in the control arm; a difference of 36·1% (95% CI: 21·3 – 50·9), p<0·001. The majority of patients with fever in the intervention arm accepted to purchase an mRDT (97·8%), of whom 58·5% tested mRDT-positive. Drug shop vendors adhered to the mRDT results, reducing over-treatment of malaria by 72·6% (95% CI: 46·7– 98·4), p<0·001) compared to drug shop vendors using presumptive diagnosis (control arm). Conclusion: Diagnostic testing with mRDTs compared to presumptive treatment of fevers implemented in registered drug shops substantially improved appropriate treatment of malaria with ACT

"Arming half-baked people with weapons!" Information enclaving among professionals and the need for a care-centred model for antibiotic use information in Uganda, Tanzania and Malawi

Background The overuse of antimicrobial medicines is a global health concern, including as a major driver of antimicrobial resistance. In many low- and middle-income countries, a substantial proportion of antibiotics are purchased over-the-counter without a prescription. But while antibiotics are widely available, information on when and how to use them is not. Objective We aimed to understand the acceptability among experts and professionals of sharing information on antibiotic use with end users – patients, carers and farmers – in Uganda, Tanzania and Malawi. Methods Building on extended periods of fieldwork amongst end-users and antibiotic providers in the three countries, we conducted two workshops in each, with a total of 44 medical and veterinary professionals, policy makers and drug regulators, in December 2021. We carried out extensive documentary and literature reviews to characterise antibiotic information systems in each setting. Results Participants reported that the general public had been provided information on medicine use in all three countries by national drug authorities, health care providers and in package inserts. Participants expressed concern over the danger of sharing detailed information on antibiotic use, particularly that end-users are not equipped to determine appropriate use of medicines. Sharing of general instructions to encourage professionally-prescribed practices was preferred. Conclusions Without good access to prescribers, the tension between enclaving and sharing of knowledge presents an equity issue. Transitioning to a client care-centred model that begins with the needs of the patient, carer or farmer will require sharing unbiased antibiotic information at the point of care

How Experiences Become Data: The Process of Eliciting Adverse Event, Medical History and Concomitant Medication Reports in Antimalarial and Antiretroviral Interaction Trials.

Accurately characterizing a drug's safety profile is essential. Trial harm and tolerability assessments rely, in part, on participants' reports of medical histories, adverse events (AEs), and concomitant medications. Optimal methods for questioning participants are unclear, but different methods giving different results can undermine meta-analyses. This study compared methods for eliciting such data and explored reasons for dissimilar participant responses. Participants from open-label antimalarial and antiretroviral interaction trials in two distinct sites (South Africa, n = 18 [all HIV positive]; Tanzania, n = 80 [86% HIV positive]) were asked about ill health and treatment use by sequential use of (1) general enquiries without reference to particular conditions, body systems or treatments, (2) checklists of potential health issues and treatments, (3) in-depth interviews. Participants' experiences of illness and treatment and their reporting behaviour were explored qualitatively, as were trial clinicians' experiences with obtaining participant reports. Outcomes were the number and nature of data by questioning method, themes from qualitative analyses and a theoretical interpretation of participants' experiences. There was an overall cumulative increase in the number of reports from general enquiry through checklists to in-depth interview; in South Africa, an additional 12 medical histories, 21 AEs and 27 medications; in Tanzania an additional 260 medical histories, 1 AE and 11 medications. Checklists and interviews facilitated recognition of health issues and treatments, and consideration of what to report. Information was sometimes not reported because participants forgot, it was considered irrelevant or insignificant, or they feared reporting. Some medicine names were not known and answers to questions were considered inferior to blood tests for detecting ill health. South African inpatient volunteers exhibited a "trial citizenship", working to achieve researchers' goals, while Tanzanian outpatients sometimes deferred responsibility for identifying items to report to trial clinicians. Questioning methods and trial contexts influence the detection of adverse events, medical histories and concomitant medications. There should be further methodological work to investigate these influences and find appropriate questioning methods