Creating equity in health research to drive more and better evidence.

Health research is rapidly changing with evidence being gathered through new agile methods. This evolution is critical but must be globally equitable so the poorest nations do not lose out. We must harness this change to better tackle the daily burden of diseases that affect the most impoverished populations and bring research capabilities to every corner of the world so that rapid and fair responses to new pathogen are possible; anywhere they appear. We must seize this opportunity to make research easier, better and more equitable. Currently too many nations are unable to generate the evidence or translate it to directly change health outcomes in their own communities. It is essential to act and harness this emerging change in how research data can be generated and shared, so that all nations sustainably gain from this development. There are positive examples to draw on from COVID-19, but we now need to act. Here we present an initiative to develop a new framework that can guide researchers in the design and execution of their studies. This highly agile system will work by adapting to risk and complexity in any given study, whilst generating quality, safe and ethical data.

Setting up a pragmatic clinical trial in a low-resource setting: A qualitative assessment of GoLBeT, a trial of podoconiosis management in Northern Ethiopia.

BACKGROUND: Clinical trials are often perceived as being expensive, difficult and beyond the capacity of healthcare workers in low-resource settings. However, in order to improve healthcare coverage, the World Health Organization (WHO) World Health Report 2013 stated that all countries need to become generators as well as recipients of data. This study is a methodological examination of the steps and processes involved in setting up the Gojjam Lymphoedema Best Practice Trial (GoLBeT; ISRCTN67805210), a highly pragmatic clinical trial conducted in northern Ethiopia. Challenges to the trial and strategies used to deal with them were explored, together with the reasons for delays. METHODOLOGY AND PRINCIPAL FINDINGS: Qualitative research methods were used to analyse emails and reports from the period between trial inception and recruitment. This analysis was complemented by interviews with key informants from the trial operational team. The Global Health Research Process Map was used as a framework against which to compare the steps involved in setting up the trial. A mini-group discussion was conducted with the trial operational team after study completion for reflection and further recommendations. This study showed that the key areas of difficulty in setting up and planning this trial were: the study design, that is, deciding on the study endpoint, where and how best to measure it, and assuring statistical power; recruitment and appropriate training of staff; planning for data quality; and gaining regulatory approvals. Collaboration, for example with statisticians, the trial steering committee, the study monitors, and members of the local community was essential to successfully setting up the trial. CONCLUSIONS AND SIGNIFICANCE: Lessons learnt from this trial might guide others planning pragmatic trials in settings where research is not common, allowing them to anticipate possible challenges and address them through trial design, planning and operational delivery. We also hope that this example might encourage similar pragmatic studies to be undertaken. Such studies are rarely undertaken or locally led, but are an accessible and efficient way to drive improved outcomes in public health.

COVID-19 en América Latina y Caribe: determinación de prioridadesen investigación y llamado a la acción / COVID-19 in Latin America and Caribbean: a determination of research priorities and call to action

Antecedentes: La Red de Salud Global estableció, en enero 2020, una comunidad de práctica para abordar la investigación en COVID-19 en países de ingresos bajos/medios. Objetivo: Identificar prioridades en investigación sobre COVID-19 que requieren atención urgente en América Latina y el Caribe (LAC) y establecer una comunidad de práctica abierta local para apoyar su implementación. Métodos: Estudio exploratorio mixto. Se analizaron los resultados específicos para LAC de una encuesta en línea (enfoque cuantitativo) que evaluó si la agenda prioritaria de investigación para COVID-19 de la OMS sigue siendo pertinente solicitando a los participantes que clasificaran sus tres principales prioridades a corto y largo plazo. Asimismo, se organizó un taller virtual abierto (enfoque cualitativo) el cual fue grabado. Se realizó un análisis temático pragmático a partir de las presentaciones de los panelistas y de las preguntas y comentarios de la audiencia. Se generó un marco de codificación mediante enfoques inductivo y luego deductivo siguiendo la agenda OMS. Resultados: Se contó con 223 participantes de 22 países. Se identificó un consenso sobre los temas de investigación e innovación prioritarios para LAC, dentro y fuera del marco de la agenda OMS, siendo una gran prioridad la necesidad de estudios de ciencias sociales para ayudar a los científicos biomédicos. Discusión: Dado que los casos siguen aumentando en LAC, consideramos que nuestros hallazgos son útiles para orientar tanto a las redes de investigación en la planificación de estudios como a los financiadores en sus decisiones para la asignación de recursos para investigación e innovación...(AU)

ZikaPLAN: addressing the knowledge gaps and working towards a research preparedness network in the Americas.

Zika Preparedness Latin American Network (ZikaPLAN) is a research consortium funded by the European Commission to address the research gaps in combating Zika and to establish a sustainable network with research capacity building in the Americas. Here we present a report on ZikaPLAN`s mid-term achievements since its initiation in October 2016 to June 2019, illustrating the research objectives of the 15 work packages ranging from virology, diagnostics, entomology and vector control, modelling to clinical cohort studies in pregnant women and neonates, as well as studies on the neurological complications of Zika infections in adolescents and adults. For example, the Neuroviruses Emerging in the Americas Study (NEAS) has set up more than 10 clinical sites in Colombia. Through the Butantan Phase 3 dengue vaccine trial, we have access to samples of 17,000 subjects in 14 different geographic locations in Brazil. To address the lack of access to clinical samples for diagnostic evaluation, ZikaPLAN set up a network of quality sites with access to well-characterized clinical specimens and capacity for independent evaluations. The International Committee for Congenital Anomaly Surveillance Tools was formed with global representation from regional networks conducting birth defects surveillance. We have collated a comprehensive inventory of resources and tools for birth defects surveillance, and developed an App for low resource regions facilitating the coding and description of all major externally visible congenital anomalies including congenital Zika syndrome. Research Capacity Network (REDe) is a shared and open resource centre where researchers and health workers can access tools, resources and support, enabling better and more research in the region. Addressing the gap in research capacity in LMICs is pivotal in ensuring broad-based systems to be prepared for the next outbreak. Our shared and open research space through REDe will be used to maximize the transfer of research into practice by summarizing the research output and by hosting the tools, resources, guidance and recommendations generated by these studies. Leveraging on the research from this consortium, we are working towards a research preparedness network.

Cost-effectiveness and social outcomes of a community-based treatment for podoconiosis lymphoedema in the East Gojjam zone, Ethiopia.

BACKGROUND: Podoconiosis is a disease of the lymphatic vessels of the lower extremities that is caused by chronic exposure to irritant soils. It results in leg swelling, commonly complicated by acute dermatolymphangioadenitis (ADLA), characterised by severe pain, fever and disability. METHODS: We conducted cost-effectiveness and social outcome analyses of a pragmatic, randomised controlled trial of a hygiene and foot-care intervention for people with podoconiosis in the East Gojjam zone of northern Ethiopia. Participants were allocated to the immediate intervention group or the delayed intervention group (control). The 12-month intervention included training in foot hygiene, skin care, bandaging, exercises, and use of socks and shoes, and was supported by lay community assistants. The cost-effectiveness analysis was conducted using the cost of productivity loss due to acute dermatolymphangioadenitis. Household costs were not included. Health outcomes in the cost-effectiveness analysis were: the incidence of ADLA episodes, health-related quality of life captured using the Dermatology Life Quality Index (DLQI), and disability scores measured using the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0). RESULTS: The cost of the foot hygiene and lymphoedema management supplies was 529 ETB (69 I$, international dollars) per person per year. The cost of delivery of the intervention as part of the trial, including transportation, storage, training of lay community assistants and administering the intervention was 1,890 ETB (246 I$) per person. The intervention was effective in reducing the incidence of acute dermatolymphangioadenitis episodes and improving DLQI scores, while there were no significant improvements in the disability scores measured using WHODAS 2.0. In 75% of estimations, the intervention was less costly than the control. This was due to improved work productivity. Subgroup analyses based on income group showed that the intervention was cost-effective (both less costly and more effective) in reducing the number of acute dermatolymphangioadenitis episodes and improving health-related quality of life in families with monthly income <1,000 ETB (130 I$). For the subgroup with family income ≥1,000 ETB, the intervention was more effective but more costly than the control. CONCLUSIONS: Whilst there is evident benefit of the intervention for all, the economic impact would be greatest for the poorest.

Global health trials methodological research agenda: results from a priority setting exercise.

BACKGROUND: Methodological research into the design, conduct, analysis and reporting of trials is essential to optimise the process. UK specialists in the field have established a set of top priorities in aid of this research. These priorities, however, may not be reflected in the needs of similar research in low- to middle-income countries (LMICs) with different healthcare provision, resources and research infrastructure. The aim of the study was to identify the top priorities for methodological research in LMICs to inform further research and ultimately to improve clinical trials in these regions. METHODS: An online, two-round survey was conducted from December 2016 to April 2017 amongst researchers and methodologists working on trials in LMICs. The first round required participants to suggest between three and six topics which they felt were priorities for trial methodological research in LMICs. The second round invited participants to grade the importance of a compulsory list of topics suggested by four or more individuals, and an optional list of the remaining topics. FINDINGS: Rounds 1 and 2 were completed by 412 and 314 participants, respectively. A wide spread of years of experience, discipline, current country of residence, origin of trials training and area of involvement in trials was reported. The topics deemed most important for methodological research were: choosing appropriate outcomes to measure and training of research staff. CONCLUSION: By presenting these top priorities we have the foundations of a global health trials methodological research agenda which we hope will foster future research in specific areas in order to increase and improve trials in LMICs.

Podoconiosis treatment in northern Ethiopia (GoLBet): study protocol for a randomised controlled trial.

BACKGROUND: Podoconiosis is one of the forgotten types of leg swelling (elephantiasis) in the tropics. Unlike the other, better-known types of leg swelling, podoconiosis is not caused by any parasite, virus or bacterium, but by an abnormal reaction to minerals found in the clay soils of some tropical highland areas. Non-governmental Organizations (NGOs) have been responsible for the development of simple treatment methods without systematic evaluation of its effectiveness. It is essential that a large scale, fully controlled, pragmatic trial of the intervention is conducted. We aim to test the hypothesis that community-based treatment of podoconiosis lymphoedema reduces the frequency of acute dermatolymphangioadenitis episodes ('acute attacks') and improves other clinical, social and economic outcomes. METHODS/DESIGN: This is a pragmatic, individually randomised controlled trial. We plan to randomly allocate 680 podoconiosis patients from the East Gojjam Zone in northern Ethiopia to one of two groups: 'Standard Treatment' or 'Delayed Treatment'. Those randomised to standard treatment will receive the hygiene and foot-care intervention from May 2015 for one year, whereas those in the control arm will be followed through 2015 and be offered the intervention in 2016. The trial will be preceded by an economic context survey and a Rapid Ethical Assessment to identify optimal methods of conveying information about the trial and the approaches to obtaining informed consent preferred by the community. The primary outcome will be measured by recording patient recall and using a simple, patient-held diary that will be developed to record episodes of acute attacks. Adherence to treatment, clinical stage of disease, quality of life, disability and stigma will be considered secondary outcome measures. Other outcomes will include adverse events and economic productivity. Assessments will be made at baseline and at 3, 6, 9 and 12 months thereafter. DISCUSSION: The evidence is highly likely to inform implementation of the new master plan for integrated control of Neglected Tropical Diseases (NTDs), in which podoconiosis is identified as one of eight NTDs prioritised for control. Potentially, an estimated 3 million patients in Ethiopia will therefore benefit from the results of this trial. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number. REGISTRATION NUMBER: ISRCTN67805210. Date of registration: 24 January 2013.

International health research monitoring: exploring a scientific and a cooperative approach using participatory action research.

OBJECTIVES: To evaluate and determine the value of monitoring models developed by the Mahidol Oxford Tropical Research Unit and the East African Consortium for Clinical Research, consider how this can be measured and explore monitors' and investigators' experiences of and views about the nature, purpose and practice of monitoring. RESEARCH DESIGN: A case study approach was used within the context of participatory action research because one of the aims was to guide and improve practice. 34 interviews, five focus groups and observations of monitoring practice were conducted. SETTING AND PARTICIPANTS: Fieldwork occurred in the places where the monitoring models are coordinated and applied in Thailand, Cambodia, Uganda and Kenya. Participants included those coordinating the monitoring schemes, monitors, senior investigators and research staff. ANALYSIS: Transcribed textual data from field notes, interviews and focus groups was imported into a qualitative data software program (NVIVO V. 10) and analysed inductively and thematically by a qualitative researcher. The initial coding framework was reviewed internally and two main categories emerged from the subsequent interrogation of the data. RESULTS: The categories that were identified related to the conceptual framing and nature of monitoring, and the practice of monitoring, including relational factors. Particular emphasis was given to the value of a scientific and cooperative style of monitoring as a means of enhancing data quality, trust and transparency. In terms of practice the primary purpose of monitoring was defined as improving the conduct of health research and increasing the capacity of researchers and trial sites. CONCLUSIONS: The models studied utilise internal and network wide expertise to improve the ethics and quality of clinical research. They demonstrate how monitoring can be a scientific and constructive exercise rather than a threatening process. The value of cooperative relations needs to be given more emphasis in monitoring activities, which seek to ensure that research protects human rights and produces reliable data.

Adaptive trial design: could we use this approach to improve clinical trials in the field of global health?

We need more clinical trials in the world's poorest regions to evaluate new drugs and vaccines, and also to find better ways to manage health issues. Clinical trials are expensive, time consuming, and cumbersome. However, in wealthier regions these limiting factors are being addressed to make trials less administrative and improve the designs. A good example is adaptive trial design. This innovation is becoming accepted by the regulators and has been taken up by the pharmaceutical industry to reduce product development times and costs. If this approach makes trials easier and less expensive surely we should be implementing this approach in the field of tropical medicine and international health? As yet this has rarely been proposed and there are few examples. There is a need for raising the awareness of these design approaches because they could be used to make dramatic improvements to clinical research in developing countries.

The challenges and opportunities of conducting a clinical trial in a low resource setting: the case of the Cameroon mobile phone SMS (CAMPS) trial, an investigator initiated trial.

Conducting clinical trials in developing countries often presents significant ethical, organisational, cultural and infrastructural challenges to researchers, pharmaceutical companies, sponsors and regulatory bodies. Globally, these regions are under-represented in research, yet this population stands to gain more from research in these settings as the burdens on health are greater than those in developed resourceful countries. However, developing countries also offer an attractive setting for clinical trials because they often have larger treatment naive populations with higher incidence rates of disease and more advanced stages. These factors can present a reduction in costs and time required to recruit patients. So, balance needs to be found where research can be encouraged and supported in order to bring maximum public health benefits to these communities. The difficulties with such trials arise from problems with obtaining valid informed consent, ethical compensation mechanisms for extremely poor populations, poor health infrastructure and considerable socio-economic and cultural divides. Ethical concerns with trials in developing countries have received attention, even though many other non-ethical issues may arise. Local investigator initiated trials also face a variety of difficulties that have not been adequately reported in literature. This paper uses the example of the Cameroon Mobile Phone SMS trial to describe in detail, the specific difficulties encountered in an investigator-initiated trial in a developing country. It highlights administrative, ethical, financial and staff related issues, proposes solutions and gives a list of additional documentation to ease the organisational process.

Beyond registration--measuring the public-health potential of new treatments for malaria in Africa.

Malaria claims over one million lives a year in some of the poorest countries of the world. Affected populations and governments cannot afford to pay for expensive new therapies. Most antimalarial treatments are purchased from local shops and administered in the home. These factors make for a complex set of requirements for any new treatment for malaria if a substantial reduction in mortality is ever to be achieved. Thankfully there are several treatments being developed, mostly within public-private partnerships. Typically, the goal of public-private partnerships is the granting of a product license, so work plans end after phase III trials. As these drugs will ultimately be used unsupervised, malaria control programme managers will require further data on safety and whether the drug is as efficacious when used outside of controlled clinical trials before allowing widespread use of these new products. These data need to be collected in highly specific phase IV programmes. We explain why public-private partnerships should extend their development plans well beyond drug registration, and set out the requirements of such a programme. We aim to generate debate and discussion so that guidelines that are internationally accepted and adhered to can be developed not only for antimalarials but for all drugs that are being developed specifically for use in resource-poor settings.