Challenges of adopting new trial designs in LMICs
Authors: Nita Bhandari, Ravi Prakash Upadhyay, Ranadip Chowdhury, Sunita Taneja
Journal: The Lancet Global Health (2021)

The Series of four papers on Clinical Trials in Global Health presents a useful understanding of adaptive and other innovative trial designs, as well as their efficiency in terms of resources and timeliness of results compared with conventional fixed randomised controlled trials. The first Series paper1Park JJH Grais RF Taljaard M et al.Urgently seeking efficiency and sustainability of clinical trials in global health.Lancet Glob Health. 2021; 9: e681-e690Summary Full Text Full Text PDF Scopus (4) Google Scholar discusses the considerations needed when implementing adaptive trial designs and master protocols, including the need to sustain research groups, underscoring the importance of designs like master protocols and platform designs in optimising efficiency and sustainability. The second Series paper2Park JJH Ford N Xavier D et al.Randomised trials at the level of the individual.Lancet Glob Health. 2021; 9: e691-e700Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar focuses on the adaptive trial design in the context of individually randomised controlled trials, and the third Series paper3Dron L Taljaard M Cheung YB et al.The role and challenges of cluster randomised trials for global health.Lancet Glob Health. 2021; 9: e701-e710Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar discusses the challenges with the use of the cluster randomised design. The final Series paper4Park JJH Mogg R Smith GE et al.How COVID-19 fundamentally has changed clinical research in global health.Lancet Glob Health. 2021; 9: e711-e720Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar uses the COVID-19 pandemic to contextualise some fundamental issues that exist in clinical trial research. The authors also emphasise the need for systematic and long-term mechanisms to enable real-time data generation and sharing for global public health use through these unconventional but promising clinical trial methods and tools. The concepts and successful examples of trial designs presented are exciting and seem encouraging. There are elements, however, for which information is insufficient, and the associated challenges will only become clearer as more experience is gained. Besides difficulties in implementation, further challenges include securing funding, considering that the funding agencies might not comprehend such designs appropriately, organisation of the research consortium to execute the master protocol and studies within it, acceptance of study designs and their nature of implementation by ethics committees and data safety boards, and statistical analysis of the data obtained, given that this analysis will probably require advanced models and these skill sets are currently scarce in low-income and middle-income countries (LMICs). It is evident that the trial designs outlined by the Series work well in pharmaceutical trials, but their application in other types of trials is scarce in LMICs, especially those using outcomes that are not readily amenable to intervention, such as growth, behaviour, and intellectual capacity. Although the benefits of these trial designs are understandable from a scientific perspective, the ethical implications of premature termination of a trial or change in interventions in an ongoing trial are not well known. One ethical ambiguity is whether comprehension can be appropriately ensured by trial coordinators in populations with low literacy when acquiring informed consent or when interventions change midway or are stopped altogether. Premature stopping of a trial might also affect legalities regarding study staff employment in some settings. Experienced ethics committees and data safety and monitoring boards that can confidently handle these designs in trials addressing a variety of research questions are needed. This is not to say that the novel designs should not be used in LMICs, but that there is a need to identify the challenges and generate solutions on several operational components before widespread implementation in these settings. It is important to acknowledge that a generalised approach does not apply to all settings. Although these study designs have been well accepted in high-income countries (HICs) in some contexts, their adoption in LMICs depends on various factors, such as the existing research environment, regulatory guidelines, and available human, economic, and infrastructural capacity. Another integral component of this Series is the theme of fostering collaborations between research groups from LMICs and HICs. Any resistance from researchers to increased collaboration requires further understanding, coupled with possible ways to alleviate this resistance by engaging with them; only then can effective solutions be identified. Due consideration should be given to challenges regarding multi-country collaborations, such as equitable distribution of funds and publication credit as well as country-specific guidelines on data sharing and transfer of biological specimens. Establishing multi-country collaborations might be time consuming because there will be issues regarding site selection, partnership agreements, and approval mechanisms for both regulatory and non-regulatory studies. The authors highlight the need for developing master protocols and implementing platform trials that could marshal research efforts in a coordinated and collaborative manner. Sustaining research infrastructure and teams are great ideas but difficult to operationalise. Funding agencies with common interests would need to harmonise in a way that sustained financial support is ensured, to allow realisation of master protocols and studies within them. There would be challenges regarding the selection of groups to be supported in the long term and for new research groups to be added. Subsequently, funders and other stakeholders will be required to deliberate extensively and set standard guidelines so that the processes are fair and transparent. We express our enthusiasm on the use of the innovative designs that will conceivably provide timely findings and ensure efficient use of resources. However, because these designs are early in their development, we believe that some aspects need greater clarity and refinement before they are used at scale by researchers in LMICs. Importantly, concurrent dissemination of findings and sharing of experiences on the use of these designs might aid in increasing acceptability. Many issues emerging from this Series are well recognised; however, achieving solutions has been difficult. We hope that this Series will reach a wider audience and provide an impetus for the adoption of novel approaches in the conduct of clinical trials and funding in LMICs. We declare no competing interests. Urgently seeking efficiency and sustainability of clinical trials in global healthThis paper shows the scale of global health research and the context in which we frame the subsequent papers in the Series. In this Series paper, we provide a historical perspective on clinical trial research by revisiting the 1948 streptomycin trial for pulmonary tuberculosis, which was the first documented randomised clinical trial in the English language, and we discuss its close connection with global health. We describe the current state of clinical trial research globally by providing an overview of clinical trials that have been registered in the WHO International Clinical Trial Registry since 2010. Full-Text PDF Open AccessRandomised trials at the level of the individualIn global health research, short-term, small-scale clinical trials with fixed, two-arm trial designs that generally do not allow for major changes throughout the trial are the most common study design. Building on the introductory paper of this Series, this paper discusses data-driven approaches to clinical trial research across several adaptive trial designs, as well as the master protocol framework that can help to harmonise clinical trial research efforts in global health research. We provide a general framework for more efficient trial research, and we discuss the importance of considering different study designs in the planning stage with statistical simulations. Full-Text PDF Open AccessThe role and challenges of cluster randomised trials for global healthEvaluating whether an intervention works when trialled in groups of individuals can pose complex challenges for clinical research. Cluster randomised controlled trials involve the random allocation of groups or clusters of individuals to receive an intervention, and they are commonly used in global health research. In this paper, we describe the potential reasons for the increasing popularity of cluster trials in low-income and middle-income countries. We also draw on key areas of global health research for an assessment of common trial planning practices, and we address their methodological shortcomings and pitfalls. Full-Text PDF Open AccessHow COVID-19 has fundamentally changed clinical research in global healthCOVID-19 has had negative repercussions on the entire global population. Despite there being a common goal that should have unified resources and efforts, there have been an overwhelmingly large number of clinical trials that have been registered that are of questionable methodological quality. As the final paper of this Series, we discuss how the medical research community has responded to COVID-19. We recognise the incredible pressure that this pandemic has put on researchers, regulators, and policy makers, all of whom were doing their best to move quickly but safely in a time of tremendous uncertainty. Full-Text PDF Open Access