Trials In Low- And Middle-income Countries Research Articles

Global Disparities in Access to Vaccine Clinical Trials: A Review of the Literature.

Vaccines are an effective tool to reduce the disease burden from infectious diseases on a population, infrastructural, and individual level. Before vaccines can be administered to populations at large, they must go through rigorous testing in the form of clinical trials. While vaccine trials can be used to assess the efficacy of interventions on a local populace as well as target local endemic diseases, most clinical trials are sponsored and conducted by companies in high-income countries (HICs). This can lead to vaccines that are not optimized for low- and middle-income countries (LMICs) and that often neglect to address diseases specific to the local population. This narrative review aims to explore the factors leading to discrepancies in the execution of and access to vaccine trials between HICs and LMICs, thus guiding future efforts in confronting them. This review was written using the literature sourced from the PubMed database and supplemented with articles from Google Scholar along with grey literature. Several themes are highlighted including poorly defined regulatory and ethical guidelines, staff shortages, lack of research infrastructure, and logistical barriers. We discuss how these challenges have affected vaccine development in various capacities through case examples of SARS-CoV-2, poliovirus, and malaria. Many challenges remain in equitable vaccine clinical trial development and implementation. Facilitating the implementation of locally sponsored vaccine clinical trials in LMICs may be one avenue to address these challenges. In doing so, LMICs can become active stakeholders in the health of their citizens by addressing endemic diseases, tailoring vaccine specifications based on local needs, and implementing wide-scale vaccine access and delivery.

Rising pharmaceutical innovation in the Global South: a landscape study

BackgroundThere is growing interest in pharmaceutical innovation in low- and middle-income countries (LMICs), but information on existing activities, capacities, and outcomes is scarce. We mapped available data at the global level, and studied the national pharmaceutical innovation systems of Bangladesh and Colombia to shed light on pharmaceutical research and development (R&D) in the Global South, including challenges and prospects, to help fill existing knowledge gaps.MethodsWe gathered and analyzed data from three types of sources: literature, semi-structured interviews with key informants, and publicly available data on R&D funding, R&D scientific capacity measured by human resources, and clinical trial activities.ResultsPharmaceutical R&D activities are occurring in many LMICs, but 16 countries have emerged as frontrunners. Investment in R&D in LMICs has increased in the past decade, particularly from middle-income countries (MICs). Capacity is also growing, with an increase in the number of research organizations and the amount of funding available from external sources. The total number of clinical trials and the proportion of trials in LMICs increased markedly, and there is also growing activity in the earlier, more innovative and riskier Phase 1 and 2 trials. Non-commercial entities comprise the majority of clinical trial funders and sponsors in LMICs. Finally, investments have borne fruit, as indicated by a number of innovative medicines developed in LMICs. The Bangladesh and Colombia country studies showed that there is still a need for both targeted R&D policies to strengthen capacities in the pharmaceutical sector, and more government support to overcome the challenges of a lack of funding and coordination among different actors.ConclusionsBy triangulating between the data sources, it was possible to paint a broad picture of who was involved in pharmaceutical R&D in LMICs, in which particular countries, for which diseases, in which R&D phases, and with what results—as well as how these trends have changed over time. Prioritizing pharmaceutical R&D is an important strategy for better meeting health needs. The trendlines are promising, but focused attention is still needed to realize the potential for greater innovation in the Global South.

The Roles of Electronic Health Records for Clinical Trials in Low- and Middle-Income Countries: Scoping Review.

Clinical trials are a crucial element in advancing medical knowledge and developing new treatments by establishing the evidence base for safety and therapeutic efficacy. However, the success of these trials depends on various factors, including trial design, project planning, research staff training, and adequate sample size. It is also crucial to recruit participants efficiently and retain them throughout the trial to ensure timely completion. There is an increasing interest in using electronic health records (EHRs)-a widely adopted tool in clinical practice-for clinical trials. This scoping review aims to understand the use of EHR in supporting the conduct of clinical trials in low- and middle-income countries (LMICs) and to identify its strengths and limitations. A comprehensive search was performed using 5 databases: MEDLINE, Embase, Scopus, Cochrane Library, and the Cumulative Index to Nursing and Allied Health Literature. We followed the latest version of the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guideline to conduct this review. We included clinical trials that used EHR at any step, conducted a narrative synthesis of the included studies, and mapped the roles of EHRs into the life cycle of a clinical trial. A total of 30 studies met the inclusion criteria: 13 were randomized controlled trials, 3 were cluster randomized controlled trials, 12 were quasi-experimental studies, and 2 were feasibility pilot studies. Most of the studies addressed infectious diseases (15/30, 50%), with 80% (12/15) of them about HIV or AIDS and another 40% (12/30) focused on noncommunicable diseases. Our synthesis divided the roles of EHRs into 7 major categories: participant identification and recruitment (12/30, 40%), baseline information collection (6/30, 20%), intervention (8/30, 27%), fidelity assessment (2/30, 7%), primary outcome assessment (24/30, 80%), nonprimary outcome assessment (13/30, 43%), and extended follow-up (2/30, 7%). None of the studies used EHR for participant consent and randomization. Despite the enormous potential of EHRs to increase the effectiveness and efficiency of conducting clinical trials in LMICs, challenges remain. Continued exploration of the appropriate uses of EHRs by navigating their strengths and limitations to ensure fitness for use is necessary to better understand the most optimal uses of EHRs for conducting clinical trials in LMICs.

Outcomes of Wilms tumor therapy in Lilongwe, Malawi, 2016-2021: Successes and ongoing research priorities.

Wilms tumor therapy in low- and middle-income countries (LMICs) relies on treatment protocols adapted to resource limitations, but these protocols have rarely been evaluated in real-world settings. Such evaluations are necessary to identify high-impact research priorities for clinical and implementation trials in LMICs. The purpose of this study was to identify highest priority targets for future clinical and implementation trials in sub-Saharan Africa by assessing outcomes of a resource-adapted treatment protocol in Malawi. We conducted a retrospective cohort study of children treated for Wilms tumor with an adapted SIOP-backbone protocol in Lilongwe, Malawi between 2016 and 2021. Survival analysis assessed variables associated with poor outcome with high potential for future research and intervention. We identified 136 patients, most commonly with stage III (n=35; 25.7%) or IV disease (n=35; 25.7%). Two-year event-free survival (EFS) was 54% for stage I/II, 51% for stage III, and 13% for stage IV. A single patient with stage V disease survived to 1year. Treatment abandonment occurred in 36 (26.5%) patients. Radiotherapy was indicated for 55 (40.4%), among whom three received it. Of these 55 patients, 2-year EFS was 31%. Of 14 patients with persistent metastatic pulmonary disease at the time of nephrectomy, none survived to 2years. Notable variables independently associated with survival were severe acute malnutrition (hazard ratio [HR]: 1.9), increasing tumor stage (HR: 1.5), and vena cava involvement (HR: 3.1). High-impact targets for clinical and implementation trials in low-resource settings include treatment abandonment, late presentation, and approaches optimized for healthcare systems with persistently unavailable radiotherapy.

Polypill Programs to Prevent Stroke and Cut Costs in Low Income Countries: Moving From Clinical Efficacy to Pragmatic Implementation.

Current projections are that the already overwhelming burden of strokes and atherosclerotic cardiovascular diseases in low- and middle-income countries (LMICs) will continue to rise over the coming decades as the prevalence of traditional vascular risk factors burgeon in these countries. Cardiovascular polypills containing combinations of antihypertensive(s), a statin, with or without aspirin or folic acid in the form of a single pill, represent a viable strategy for both primary and secondary prevention of atherosclerotic cardiovascular diseases in LMICs. Large multicenter trials in LMIC and high-income country (HIC) settings have now clearly demonstrated the beneficial effects of the cardiovascular polypill versus placebo (or usual care) in reducing primary stroke risk by 50%. For survivors of a recent myocardial infarction residing in HICs, the polypill reduced risk of major cardiovascular events by 25% due to improved treatment adherence. Data on the clinical efficacy of the polypill for secondary stroke prevention are scanty both in HICs and LMICs. Cost-effectiveness analyses data from LMICs suggest cost savings with the polypill for primary and secondary prevention of stroke and atherosclerotic cardiovascular diseases. However, major contextual barriers in LMICs need to be surmounted through mixed methods research and hybrid clinical trials to assess its real-world effectiveness, before the adoption of the polypill for primary and secondary atherosclerotic cardiovascular disease prevention in routine clinical practice.

Alzheimer disease clinical trials in low and middle income countries: A call for globalization of clinical trials

AbstractBackgroundIn the absence of clinically meaningful disease‐modifying treatments, the number of adults with dementia worldwide is projected to more than triple. Much of this increase will occur in low and middle‐income countries (LMICs); by 2050, 68% of adults living with dementia will be in LMICs. However, there is a gross under‐representation of LMICs in historical and contemporary AD clinical trial platforms.MethodsWe aimed to determine the global distribution of dementia clinical trials and identify existing barriers for conducting AD clinical trials in LMICs. Our primary data sources to identify trial distribution in LMICs included ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform. Data analysis included number of clinical trials per country, regional distribution, funding source, study phase (1, 1/2, 2, 2/3, or 3), and annual growth rate by region relative to population density. An additional systematic review search and expert consensus was conducted to identify barriers for conducting clinical trials in LMICs.ResultAmong 1737 dementia interventional trials, only 17.2% have been or are conducted in LMIC (figure 1). LMICs trial sites participated/conducted 23.6% and 10.9% of phase 3 and phase 1 trials, respectively. We identified several limitations for trial implementation including lack of financial resources, low industry presence, regulatory obstacles and operational barriers, especially related to resources in neuroimaging. Two successful international trials platforms (Dominantly Inherited Alzheimer Network‐Trials Unit [DIAN‐TU] and Worldwide FINGERS) have been able to expand into Latin American countries creating a regional network for trial implementation.ConclusionAlthough LMICs bear the greatest burden of AD in the world, substantial development of clinical trial platforms to address this inequity is lacking. Ongoing LMICs regional trial platforms (e.g., DIAN‐TU and LatAm‐FINGERS) may shed light on alternative strategies to overcome existing barriers and highlight the need for a more thoughtful approach to increase diverse representation in AD clinical trials and expand access to LMIC.

Advancing Posttraumatic Stress Disorder Diagnosis and the Treatment of Trauma in Humanitarian Emergencies via Mobile Health: Protocol for a Proof-of-Concept Nonrandomized Controlled Trial.

BackgroundDecentralized health systems in low- and middle-income countries (LMICs) affected by humanitarian crises lack resources and a qualified workforce to attend to the overwhelming demand for mental health care in emergencies. Innovative approaches that are safe, cost-effective, and scalable are needed to address the burden of traumatic stress caused by emergencies. High mobile phone ownership rates combined with the precision of neural, cognitive, and biometric measures of trauma and their feasible integration with artificial intelligence makes digital app interventions a promising pathway to promote precision diagnosis and high-impact care.ObjectiveThis study aimed to advance methods for the objective diagnosis and treatment of trauma in emergencies across LMICs by examining neural, cognitive, and biometric markers and the efficacy of the eResilience app, a neuroscience-informed mobile health mental health app intervention, via changes in clinical symptomatology, cognitive performance, and brain activity.MethodsTrauma-exposed African refugees residing in Australia were selected for this study. A research software version of the eResilience app with advanced monitoring capabilities was designed for this trial. Participants completed the eResilience app at home during a 7-day period. Clinical, cognitive, and electrophysiological data were collected at baseline, along with posttest measurements to examine biomarkers of trauma and the efficacy of the proposed digital intervention for the treatment of trauma and its potential outcomes, including depression, anxiety, physical symptoms, self-harm, substance misuse, and cognitive impairment. In addition, biofeedback, well-being, and subjective stress data points were collected via the app during the treatment week, followed by clinical interviews at 1, 3, 6, and 12 months after the intervention.ResultsData collection was conducted between 2018 and 2020. A total of 100 participants exposed to war were screened; 75 (75%) were enrolled and assigned to a trauma-exposed control (38/75, 51%) or posttraumatic stress disorder condition (37/75, 49%); and 70 (70%) completed all baseline, treatment, and posttest assessments. A total of 89% (62/70) of those who completed the intervention opted to enroll in the 3-, 6-, and 12-month follow-ups. Data collection is complete. As of May 2022, the results of all proposed analyses are being prepared for publication. If proven efficacious, this proof-of-concept clinical trial will inform fully powered randomized clinical trials in LMICs to further develop artificial intelligence–powered, app-based diagnostic and prognostic features and determine the app’s cross-cultural efficacy for the treatment of trauma in emergency settings.ConclusionsThis protocol provides researchers with a comprehensive background of the study rationale, a detailed guideline for replication studies interested in examining the feasibility and efficacy of the eResilience app across varied demographics, and a robust framework for investigating low-cost objective diagnostic markers in mental health interventions. Methodological limitations and suggestions are also provided.Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12616001205426; https://tinyurl.com/yckwc4d7International Registered Report Identifier (IRRID)RR1-10.2196/38223

Setting-up an Ebola vaccine trial in a remote area of the Democratic Republic of the Congo: Challenges, mitigations, and lessons learned

Since the largest Ebola outbreak in West Africa (2013–2016) highlighted the potential threat of the Ebola virus to the world, several vaccines have been under development by different pharmaceutical companies. To obtain vaccine licensure, vaccine trials assessing the safety, immunogenicity and efficacy of new vaccines among different populations (e.g. different in age, gender, race, and ethnicity) play a crucial role. However, while this deadly disease mainly affects Central and West Africa, clinical trial regulations are becoming increasingly complex and consequently more expensive, influencing the affected low- and middle-income countries (LMICs) in performing high quality clinical trials. Consequently, the completion of such trials in LMICs takes more time and vaccines and drugs take longer to be licensed. To overcome some of the obstacles faced, the EBOVAC3 consortium, funded by the European Union’s Innovative Medicines Initiative and the Coalition for Epidemic Preparedness Innovations, enabled high quality vaccine trials in Central and West Africa through extensive North-South collaborations. In this article, the encountered challenges, mitigations, recommendations and lessons learned from setting-up an Ebola vaccine trial in a remote area of the Democratic Republic of Congo are presented. These challenges are grouped into eight categories: (1) Regulatory, political and ethical, (2) Trial documents, (3) International collaborations, (4) Local trial staff, (5) Community engagement and sensitization, (6) Logistics, (7) Remoteness and climate conditions, (8) Financial. By sharing the encountered challenges, implemented mitigations and lessons learned for each of these categories, we hope to prepare and inform other researchers aspiring a well-functioning clinical trial unit in similar remote settings in LMICs. ClinicalTrials.gov identifier: NCT04186000.

Therapeutic Hypothermia for Neonatal Encephalopathy in Low- and Middle-Income Countries: A Meta-Analysis

Background: Perinatal asphyxia and hypoxic-ischemic encephalopathy (HIE) represent substantial sources of neonatal morbidity and mortality in low- and middle-income countries (LMICs), leading to high rates of adverse long-term neurological outcomes. Methods: A systematic review with meta-analysis of randomized controlled trials in LMICs was conducted. PubMed, Scopus, Web of Science, CENTRAL, ClinicalTrials.gov, and Google Scholar were searched from inception to August 20, 2021. The population of the study consisted of neonates with gestational age ≥34 weeks and HIE. The main endpoints were overall mortality and the composite outcome of death or severe disability. The certainty of evidence was evaluated with the GRADE approach. Results: Ten studies were included comprising 1,293 neonates. Some concerns of bias were raised due to the nonblinded nature of the intervention. The risk of death was similar between the two groups (risk ratio [RR]: 0.78, 95% confidence interval [CI]: 0.52–1.18). No significant differences were observed in the composite outcome of death or severe disability between the two groups (RR: 0.78, 95% CI: 0.56–1.10, very low quality of evidence). Furthermore, no significant differences were observed in the endpoints of sepsis, shock, acute kidney injury, major arrhythmia, and length of hospital stay. Therapeutic hypothermia was associated with significantly higher risk of thrombocytopenia (RR: 2.13, 95% CI: 1.34–3.38) and clinically significant hemorrhage (RR: 1.57, 95% CI: 1.25–1.97). Conclusion: Therapeutic hypothermia probably results in little to no difference in clinical outcomes among neonates with HIE in LMICs. Further large-scale research targeting proper patient selection is needed to elucidate the utility of therapeutic hypothermia in resource-limited settings. Protocol Registration: The protocol of the study has been prospectively registered by Prospero, CRD42021272284.

Moderator effects in a randomized controlled trial of the Common Elements Treatment Approach (CETA) for intimate partner violence and hazardous alcohol use in Zambia

BackgroundIntimate partner violence (IPV) and hazardous alcohol use are prevalent and co-occurring problems in low- and middle-income countries (LMICs). While limited evidence suggests that cognitive behavioral therapy (CBT) interventions can help address these problems, few randomized trials in LMICs have investigated moderators of treatment effectiveness. This study explores moderating factors impacting responsiveness to a CBT-based intervention for IPV and hazardous alcohol use among couples in Zambia. MethodsData were obtained from a completed randomized trial of a CBT-based intervention, the Common Elements Treatment Approach (CETA), among 248 couples in Lusaka. Female experiences of IPV and male alcohol use were measured at baseline and 12 months post-baseline. Mixed effects regression models were used to evaluate each moderator: age, educational attainment, employment status, marital status, physical disability, HIV status, trauma exposure, depression, post-traumatic stress disorder, alcohol use disorder, and substance use. ResultsTreatment effectiveness for male alcohol use was moderated by female substance use, with greater reductions among men whose partners reported using non-alcohol substances (e.g., cannabis) (p < 0.01). Other marginally significant moderators (p < 0.15) of change in male alcohol use included female education and male depression, substance use, and moderate-to-severe alcohol use at baseline. Female HIV status and depression were marginally significant moderators of change in IPV. ConclusionsThis study suggests that CETA may be especially effective for highly symptomatic individuals with comorbid mental and behavioral health problems, a promising finding given that such comorbidity is widespread in LMICs. Psychotherapeutic treatments that can flexibly and simultaneously address co-occurring problems are needed.

Hand-washing promotion for preventing diarrhoea.

BackgroundDiarrhoea accounts for 1.8 million deaths in children in low‐ and middle‐income countries (LMICs). One of the identified strategies to prevent diarrhoea is hand washing.ObjectivesTo assess the effects of hand‐washing promotion interventions on diarrhoeal episodes in children and adults.Search methodsWe searched CENTRAL, MEDLINE, Embase, nine other databases, the World Health Organization (WHO) International Clinical Trial Registry Platform (ICTRP), and metaRegister of Controlled Trials (mRCT) on 8 January 2020, together with reference checking, citation searching and contact with study authors to identify additional studies.Selection criteriaIndividually‐randomized controlled trials (RCTs) and cluster‐RCTs that compared the effects of hand‐washing interventions on diarrhoea episodes in children and adults with no intervention.Data collection and analysisThree review authors independently assessed trial eligibility, extracted data, and assessed risks of bias. We stratified the analyses for child day‐care centres or schools, community, and hospital‐based settings. Where appropriate, we pooled incidence rate ratios (IRRs) using the generic inverse variance method and a random‐effects model with a 95% confidence interval (CI). We used the GRADE approach to assess the certainty of the evidence.Main resultsWe included 29 RCTs: 13 trials from child day‐care centres or schools in mainly high‐income countries (54,471 participants), 15 community‐based trials in LMICs (29,347 participants), and one hospital‐based trial among people with AIDS in a high‐income country (148 participants). All the trials and follow‐up assessments were of short‐term duration.Hand‐washing promotion (education activities, sometimes with provision of soap) at child day‐care facilities or schools prevent around one‐third of diarrhoea episodes in high‐income countries (incidence rate ratio (IRR) 0.70, 95% CI 0.58 to 0.85; 9 trials, 4664 participants, high‐certainty evidence) and may prevent a similar proportion in LMICs, but only two trials from urban Egypt and Kenya have evaluated this (IRR 0.66, 95% CI 0.43 to 0.99; 2 trials, 45,380 participants; low‐certainty evidence). Only four trials reported measures of behaviour change, and the methods of data collection were susceptible to bias. In one trial from the USA hand‐washing behaviour was reported to improve; and in the trial from Kenya that provided free soap, hand washing did not increase, but soap use did (data not pooled; 3 trials, 1845 participants; low‐certainty evidence).Hand‐washing promotion among communities in LMICs probably prevents around one‐quarter of diarrhoea episodes (IRR 0.71, 95% CI 0.62 to 0.81; 9 trials, 15,950 participants; moderate‐certainty evidence). However, six of these nine trials were from Asian settings, with only one trial from South America and two trials from sub‐Saharan Africa. In seven trials, soap was provided free alongside hand‐washing education, and the overall average effect size was larger than in the two trials which did not provide soap (soap provided: RR 0.66, 95% CI 0.58 to 0.75; 7 trials, 12,646 participants; education only: RR 0.84, 95% CI 0.67 to 1.05; 2 trials, 3304 participants). There was increased hand washing at major prompts (before eating or cooking, after visiting the toilet, or cleaning the baby's bottom) and increased compliance with hand‐hygiene procedure (behavioural outcome) in the intervention groups compared with the control in community trials (data not pooled: 4 trials, 3591 participants; high‐certainty evidence).Hand‐washing promotion for the one trial conducted in a hospital among a high‐risk population showed significant reduction in mean episodes of diarrhoea (1.68 fewer) in the intervention group (mean difference −1.68, 95% CI −1.93 to −1.43; 1 trial, 148 participants; moderate‐certainty evidence). Hand‐washing frequency increased to seven times a day in the intervention group versus three times a day in the control arm in this hospital trial (1 trial, 148 participants; moderate‐certainty evidence).We found no trials evaluating the effects of hand‐washing promotions on diarrhoea‐related deaths or cost effectiveness.Authors' conclusionsHand‐washing promotion probably reduces diarrhoea episodes in both child day‐care centres in high‐income countries and among communities living in LMICs by about 30%. The included trials do not provide evidence about the long‐term impact of the interventions.

In-vitro diagnostic point-of-care tests in paediatric ambulatory care: A systematic review and meta-analysis.

Paediatric consultations form a significant proportion of all consultations in ambulatory care. Point-of-care tests (POCTs) may offer a potential solution to improve clinical outcomes for children by reducing diagnostic uncertainty in acute illness, and streamlining management of chronic diseases. However, their clinical impact in paediatric ambulatory care is unknown. We aimed to describe the clinical impact of all in-vitro diagnostic POCTs on patient outcomes and healthcare processes in paediatric ambulatory care. We searched MEDLINE, EMBASE, Pubmed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science from inception to 29 January 2020 without language restrictions. We included studies of children presenting to ambulatory care settings (general practice, hospital outpatient clinics, or emergency departments, walk-in centres, registered drug shops delivering healthcare) where in-vitro diagnostic POCTs were compared to usual care. We included all quantitative clinical outcome data across all conditions or infection syndromes reporting on the impact of POCTs on clinical care and healthcare processes. Where feasible, we calculated risk ratios (RR) with 95% confidence intervals (CI) by performing meta-analysis using random effects models. We included 35 studies. Data relating to at least one outcome were available for 89,439 children of whom 45,283 had a POCT across six conditions or infection syndromes: malaria (n = 14); non-specific acute fever 'illness' (n = 7); sore throat (n = 5); acute respiratory tract infections (n = 5); HIV (n = 3); and diabetes (n = 1). Outcomes centred around decision-making such as prescription of medications or hospital referral. Pooled estimates showed that malarial-POCTs (Plasmodium falciparum) better targeted antimalarial treatment by reducing over-treatment by a third compared to usual care (RR 0.67; 95% CI [0.58 to 0.77], n = 36,949). HIV-POCTs improved initiating earlier antiretroviral therapy compared to usual care (RR, 3.11; 95% CI [1.55 to 6.25], n = 912). Across the other four conditions, there was limited evidence for the benefit of POCTs in paediatric ambulatory care except for acute respiratory tract infections (RTI) in low-and-middle-income countries (LMICs), where POCT C-Reactive Protein (CRP) may reduce immediate antibiotic prescribing by a third (risk difference, -0.29 [-0.47, -0.11], n = 2,747). This difference was shown in randomised controlled trials in LMICs which included guidance on interpretation of POCT-CRP, specific training or employed a diagnostic algorithm prior to POC testing. Overall, there is a paucity of evidence for the use of POCTs in paediatric ambulatory care. POCTs help to target prescribing for children with malaria and HIV. There is emerging evidence that POCT-CRP may better target antibiotic prescribing for children with acute RTIs in LMIC, but not in high-income countries. Research is urgently needed to understand where POCTs are likely to improve clinical outcomes in paediatric settings worldwide.

Effectiveness of interventions for dementia in low- and middle-income countries: protocol for a systematic review, pairwise and network meta-analysis

IntroductionThere are more people living with dementia in low- and middle-income countries (LMICs) than in high-income countries. Evidence-based interventions to improve the lives of people living with dementia and their...

Global Breast Cancer Research: Moving Forward.

Breast cancer is a major global health problem and major cause of mortality. Although mortality trends are declining in high-income countries, trends are increasing in low- and middle-income countries (LMICs). Addressing global breast cancer research is a challenging endeavor, as notable disparities and extremely heterogeneous realities exist in different regions across the world. Basic global cancer health care needs have been addressed by the World Health Organization's (WHO) proposed list of essential medicines and by resource-stratified guidelines for screening and treatment. However, specific strategies are needed to address disparities in access to health care, particularly access to new therapies. Discussions about global research in breast cancer should take into account the ongoing globalization of clinical trials. Collaboration fostered by well-established research organizations in North America and Europe is essential for the development of infrastructure and human resources in LMICs so that researchers in these countries can begin to address regional questions. Specific challenges that impact the future of global breast cancer research include increasing the availability of trials in LMICs, developing strategies to increase patient participation in clinical trials, and creation of clear guidelines for the development of real-world evidence-based research. The main objective of this review is to encourage the discussion of challenges in global breast cancer research with the hope that collectively we will be able to generate workable proposals to advance the field.

Disparities in Breast, Lung, and Cervical Cancer Trials Worldwide.

PurposeAs cancer burden has risen worldwide, physicians, patients, and their advocates have become aware that the clinical cancer trial research paradigm is not ubiquitous. Furthermore, the number and characteristics of trials that are registered in low- and middle-income countries (LMICs) compared with that in high-income countries (HICs) are unknown.MethodsWe collected retrospective data on trials for breast, lung, and cervical cancer registered in ClinicalTrials.gov or with the WHO International Clinical Trial Registry Platform between 2010 and 2017. The data were then classified as trials within LMICs or HICs using definitions from the World Bank.ResultsIncluded in these analyses were 6,710 trials, of which 3,164 (47%) were breast cancer trials, 3,283 (49%) were lung cancer trials, and 263 (4%) were cervical cancer trials. There were 1,951 (29%) trials from LMICs and 4,759 (71%) trials from HICs (P < .001). Although the proportion of phase III trials in HICs versus LMICs was similar (18% v 17%; P = .66), the number of phase I trials in LMICs was significantly lower than that of HICs (20% v 2%; P < .001). For several LMICs with the highest mortality-to-incidence ratios for breast, lung, or cervical cancer, there were no cancer trials registered in the registration data bases searched for this work.ConclusionThere are differences in access to cancer clinical trials in LMICs compared with HICs. Several factors, such as excessive cost and a lack of infrastructure and expertise, may explain these differences.

THE INTERNATIONAL GOOD CLINICAL PRACTICES GUIDELINES: TIME FOR A REVISION?

BackgroundThe Good Clinical Practices (GCP) codes of the World Health Organization and the International Conference of Harmonization set international standards for clinical research. But critics argue that they were written...

A meta-analysis of nutrition interventions on mental development of children under-two in low- and middle-income countries.

Interventions to improve nutritional status of young children in low- and middle-income countries (LMIC) may have the added benefit of improving their mental and motor development. This meta-analysis updates and goes beyond previous ones by answering two important questions: (1) do prenatal and postnatal nutritional inputs improve mental development, and (2) are effects on mental development associated with two theoretically interesting mediators namely physical growth and motor development? The meta-analysis of articles on Medline, PsycINFO, Global Health and Embase was limited to randomized trials in LMICs, with mental development of children from birth to age two years as an outcome. The initial yield of 2689 studies was reduced to 33; 12 received a global quality rating of strong. Of the 10 prenatal and 23 postnatal nutrition interventions, the majority used zinc, iron/folic acid, vitamin A or multiple micronutrients, with a few evaluating macronutrients. The weighted mean effect size, Cohen's d (95% CI) for prenatal and postnatal nutrition interventions on mental development was 0.042 (-0.0084, 0.092) and 0.076 (0.019, 0.13), respectively. Postnatal supplements consisting of macronutrients yielded an effect size d (95% CI) of 0.14 (0.0067, 0.27), multiple micronutrients 0.082 (-0.012, 0.18) and single micronutrients 0.058 (-0.0015, 0.12). Motor development, but not growth status, effect sizes were significantly associated with mental development in postnatal interventions. In summary, nutrition interventions had small effects on mental development. Future studies might have greater effect if they addressed macronutrient deficiencies combined with child stimulation and hygiene and sanitation interventions.

Hand washing promotion for preventing diarrhoea

BackgroundDiarrhoea accounts for 1.8 million deaths in children in low‐ and middle‐income countries (LMICs). One of the identified strategies to prevent diarrhoea is hand washing.ObjectivesTo assess the effects of hand washing promotion interventions on diarrhoeal episodes in children and adults.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register (27 May 2015); CENTRAL (published in the Cochrane Library 2015, Issue 5); MEDLINE (1966 to 27 May 2015); EMBASE (1974 to 27 May 2015); LILACS (1982 to 27 May 2015); PsycINFO (1967 to 27 May 2015); Science Citation Index and Social Science Citation Index (1981 to 27 May 2015); ERIC (1966 to 27 May 2015); SPECTR (2000 to 27 May 2015); Bibliomap (1990 to 27 May 2015); RoRe, The Grey Literature (2002 to 27 May 2015); World Health Organization (WHO) International Clinical Trial Registry Platform (ICTRP), metaRegister of Controlled Trials (mRCT), and reference lists of articles up to 27 May 2015. We also contacted researchers and organizations in the field.Selection criteriaIndividually randomized controlled trials (RCTs) and cluster‐RCTs that compared the effects of hand washing interventions on diarrhoea episodes in children and adults with no intervention.Data collection and analysisThree review authors independently assessed trial eligibility, extracted data, and assessed risk of bias. We stratified the analyses for child day‐care centres or schools, community, and hospital‐based settings. Where appropriate, incidence rate ratios (IRR) were pooled using the generic inverse variance method and random‐effects model with 95% confidence intervals (CIs). We used the GRADE approach to assess the quality of evidence.Main resultsWe included 22 RCTs: 12 trials from child day‐care centres or schools in mainly high‐income countries (54,006 participants), nine community‐based trials in LMICs (15,303 participants), and one hospital‐based trial among people with acquired immune deficiency syndrome (AIDS) (148 participants).Hand washing promotion (education activities, sometimes with provision of soap) at child day‐care facilities or schools prevents around one‐third of diarrhoea episodes in high income countries (rate ratio 0.70; 95% CI 0.58 to 0.85; nine trials, 4664 participants, high quality evidence), and may prevent a similar proportion in LMICs but only two trials from urban Egypt and Kenya have evaluated this (rate ratio 0.66, 95% CI 0.43 to 0.99; two trials, 45,380 participants, low quality evidence). Only three trials reported measures of behaviour change and the methods of data collection were susceptible to bias. In one trial from the USA hand washing behaviour was reported to improve; and in the trial from Kenya that provided free soap, hand washing did not increase, but soap use did (data not pooled; three trials, 1845 participants, low quality evidence).Hand washing promotion among communities in LMICs probably prevents around one‐quarter of diarrhoea episodes (rate ratio 0.72, 95% CI 0.62 to 0.83; eight trials, 14,726 participants, moderate quality evidence). However, six of these eight trials were from Asian settings, with only single trials from South America and sub‐Saharan Africa. In six trials, soap was provided free alongside hand washing education, and the overall average effect size was larger than in the two trials which did not provide soap (soap provided: rate ratio 0.66, 95% CI 0.56 to 0.78; six trials, 11,422 participants; education only: rate ratio: 0.84, 95% CI 0.67 to 1.05; two trials, 3304 participants). There was increased hand washing at major prompts (before eating/cooking, after visiting the toilet or cleaning the baby's bottom), and increased compliance to hand hygiene procedure (behavioural outcome) in the intervention groups than the control in community trials (data not pooled: three trials, 3490 participants, high quality evidence).Hand washing promotion for the one trial conducted in a hospital among high‐risk population showed significant reduction in mean episodes of diarrhoea (1.68 fewer) in the intervention group (Mean difference 1.68, 95% CI 1.93 to 1.43; one trial, 148 participants, moderate quality evidence). There was increase in hand washing frequency, seven times per day in the intervention group versus three times in the control in this hospital trial (one trial, 148 participants, moderate quality evidence).We found no trials evaluating or reporting the effects of hand washing promotions on diarrhoea‐related deaths, all‐cause‐under five mortality, or costs.Authors' conclusionsHand washing promotion probably reduces diarrhoea episodes in both child day‐care centres in high‐income countries and among communities living in LMICs by about 30%. However, less is known about how to help people maintain hand washing habits in the longer term.22 March 2019Update pendingAuthors currently updatingThe update is due to be published in 2019.

Global women's health: current clinical trials in low- and middle-income countries.

Clinical trials in low- and middle-income countries (LMICs) are necessary to develop evidence-based approaches to improve women's health. Understanding what research is currently being conducted will allow the identification of research gaps, avoidance of duplication, planning of future studies, collaboration amongst research groups, and geographical targeting for research investments. To provide an overview of active women's health trials in LMICs. The World Health Organization's International Clinical Trials Registry Platform was searched for trials registered between 1 April 2012 and 31 March 2014. Selected trials were randomised, conducted in LMICs, active, and with a women's health intervention or a significant outcome for the woman. Two reviewers extracted data. Analysis included geographical spread, speciality areas, pre-enrolment registration, study size, and funders. Of the 8966 records, 509 were eligible for inclusion. Gynaecology trials made up 57% of the research, whereas the remaining 43% of trials were in obstetrics. Research activity focused on fertility (17%), the antenatal period (15%), benign gynaecology (14%), intrapartum care (9%), and pre-invasive disease and cancers (8%). The majority of trials (84%) took place in middle-income countries (MICs). In low-income countries (LICs) 83% of research investigated obstetrics, and in MICs 60% of research investigated gynaecology. Most trials (80%) had a sample size of 500 or fewer participants. The median size of trials in LICs was 815 compared with 128 in MICs. Pre-enrolment registration occurred in 54% of trials. The majority (62%) of trials were funded locally. Many LMICs are active in women's health research. The majority of registered trials are located in MICs; however, the trials in LICs are often larger. The focus of research in MICs may be driven by local priorities and funding, with fertility being highly researched. In LICs, pregnancy is the focus, perhaps reflecting the international prioritisation of maternal health.

Transfer of evidence‐based medical guidelines to low‐ and middle‐income countries

keywords evidence-based medicine, guidelines, tropical medicine, low- and middle-income countriesEvidence-based medicine is widely accepted to guidemedical recommendations: clinical or diagnostic guidelinesare developed on the grounds of the best available data,systematic reviews and sound clinical understanding(Sackett et al. 1996). But occasionally the quality of theevidence may not be as good as expected (Kett et al. 2011).In the absence of high-quality data, one has to rely oninformation generated through studies with suboptimaldesigns and based on mere empirical – frequentlysubjective – experience. Important medical problemsoccurring in high-income countries can, depending on site-specific conditions, provoke much more severe challengeswhen occurring in low- and middle-income countries(LMICs).Most clinical guidelines not directly related to tropicalmedicine cannot or do not consider trials performed inLMICs, because, for many medical conditions, such trialshave either not been conducted there or are of questionablequality. Technical prerequisites, ethical issues, infrastruc-tural constraints, overburdened health systems and, fre-quently, the lack of appropriate funding prevent successfuland meaningful realization of clinical trials in LMICs. As aresult, conclusions on the applicability of guidelines thathave proven valuable in high-income countries are difficultto draw for LMICs.The clinical guideline for haemodynamic support ofpaediatric and neonatal septic shock proposed by theAmerican College of Critical Care Medicine (Brierley et al.2009), for example, suggests early fluid administration as aprimary therapeutic measure. And, if applicable, thismeasure should be taken in conjunction with intercon-nected measures such as inotropic support, close haemo-dynamic monitoring and mechanical ventilation. Thisguideline and the algorithm proposed are largely acceptedin high-income countries.Severefebrileconditions causingasystemicinflammatoryresponse syndrome are important causes of morbidity andmortality in LMICs. This applies particularly to childrenand fevers with underlying causes such as malaria andsepticaemia. In LMICs, diagnostic resources and accurateclinical monitoring, including treatment options, are oftenlimited. Recently a multicentre, open, randomized con-trolledtrial onfluidmanagementinKenyan,TanzanianandUgandan children was designed to apply fluid boluses assuggested by the aforementioned guideline (Maitland et al.2011). The children were suffering from severe febrileillnesses complicated by impaired consciousness and/orrespiratory distress and showed evidence of impairedperfusion. Upon admission to hospital, they were treatedwith boluses of either albumin or saline. In addition, thechildren received maintenance fluids and, in cases ofhaemoglobin levels below 5 g/dl, whole blood transfusionsof 20 ml/kg over a period of 4 h. Bolus volumes wereincreased after a protocol amendment. The result of thestudy was that fluid boluses significantly raised the 48-hmortality, andas a consequence, the trial had to bestopped.The study was performed in ‘typical African hospitals,which have no intensive care facilities’ (Maitland et al.2011). Although complications due to fluid overload werereported to be rare, the outcome of the study and its haltingahead of schedule recommended by the Data and SafetyMonitoring Committee indicate that potential complica-tions were not perceived in due time, most likely due to thelack of diagnostic means and merely clinical assessments.The investigators singled out and evaluated one specificintervention from the set of complex and interconnectedprocedures outlined in the guideline. This important studyraises the fundamental question about the applicability ofguidelines in LMICs when data were generated in high-income settings and vice versa, in addition to a number ofweighty arguments put forward by others (Southall &Samuels 2011).Chinnock et al. (2005) have emphasized that ‘the rele-vance of systematic reviews to frontline health care