Clinical Trial Operations In Low- And Middle-Income Countries: 5 Keys To Success

By Caitlin Ciavarro, Bill & Melinda Gates Medical Research Institute

Throughout my career working on clinical trials that have evaluated vaccine candidates and experimental compounds, I have observed that the most intensive part of any clinical trial is the launch effort. The work needed to identify, set up, and collaborate with each trial site — so that operations run smoothly — is integral to any successful program.

At the Gates Medical Research Institute, we are working to find new interventions to prevent and treat tuberculosis (TB), malaria, and other neglected diseases that primarily impact low- and middle-income countries (LMICs). To best serve the communities impacted by these diseases, we conduct our clinical trials in LMICs, but this brings added layers of complexities — especially for the later-stage trials in which we collaborate with dozens of trial sites in different parts of the world.

Clinical operations should be involved in the earliest stages of trial design, when we draw up the clinical trial protocol and synopsis — basically, the blueprint of how we are going to run the trial. The clinical trial team will then be prepared for successfully operationalizing the study and can start to work through the different pieces that need to come together for the start of the trial.

Five Best Practices For Clinical Operations

Our teams focus on five best practices for planning and then implementing clinical trial operations in LMICs. These have led us to successful outcomes even when situations become unpredictable.

1. Visit the countries where you will be working, early and often.

Until you see the locations in person, you really cannot fully understand the settings in which these sites are working or the ingenuity, expertise, and caring demonstrated by facility personnel.

For example, one of our trials evaluated a site in a middle-income country that serves an informal community, one that sprung up on the side of a busy road. Their facility, which was a potential vaccine trial site, was initially launched to provide healthcare but expanded to include a multidimensional youth program including educational and leadership initiatives and a recreation program. As both an adolescent health center and vaccine trial site for high-school aged participants, the study space for participants to do their homework while attending clinic visits was something that we took note of as a best practice, a case study in serving the community that participates in a trial.

In some cases, where populations of potential trial participants access healthcare from facilities that could become trial sites, we support these facilities in building capacity and capability so that they can join our trials. For one clinical drug trial, a Phase 2 located in South Africa, two sites met most of our selection criteria in terms of participant population and therapeutic area expertise. But we had to work closely with them to make sure that they had the proper environmental controls in place to allow for them to house study participants with active tuberculosis, who needed to receive in-patient care at the facility during the study.

In other cases, we find facilities that are already optimal. But we only know for certain once we visit the sites, get acquainted with staff, and understand the needs of the local communities. For another clinical trial of a vaccine candidate, a Phase 3 trial with 60 sites across seven countries, almost all sites involved met all selection criteria, with only minor needs, such as renting refrigerators to store the compounds at the proper temperature.

2. Listen; don’t just disseminate instructions.

Understanding the context of your operations at each trial site is essential to success. This is a requirement for all clinical trials regardless of whether the sites are located in high-income countries (HICs) or LMICs, and you cannot gain this understanding without listening to what your partners tell you.

At a minimum in HICs, dialogues are needed with patient advisory groups and similar entities, and these conversations should start with listening to them explain the community history and current political and social setting. Working in LMICs, we have found the greatest value when we communicate with the community advisory boards and with more local groups, including village elders and others, who can provide insights and help the trial run smoothly, from recruitment through to clinical follow-up.

For each trial site, we partner with the principal investigators (PIs) and facility staff early in the process and we ensure continuous feedback throughout the trial. Our collaborations with the site PIs start as we develop the trial synopsis and continue through to the final protocol approval — their input is crucial to making sure we are working in the best interests of the trial participants.

We also establish robust scientific advisory boards, soliciting feedback from the experiences of a wide variety of researchers.

In a particular trial site, our community research organization (CRO) partner proposed one strategy for ethics committee submission and the site PIs proposed another. After trying the CRO partner’s strategy and encountering delays, we connected both parties and were able to come to alignment and move ahead with the PIs’ strategy and a more straightforward path to approval.

3. Develop backup strategies.

As part of our planning process, we ensure that there are contingencies in place to continue operations and oversight in case of natural disasters or political or social turmoil. After Hurricane Katrina hit the U.S. in 2005, for example, having a disaster plan became a common practice, no matter how wealthy the country your trial was situated in.

Many of the tools that evolved during the COVID-19 pandemic can be leveraged as backup plans to be used in unpredictable situations, such as maintaining secure computers (file transfer protocol or FTP sites) that can be accessed remotely for sharing redacted source data, coordinating video visits when conditions make in-person meetings less feasible, and converting investigator study files to electronic records.

For one recent study evaluating a potential TB therapy, we used video observed therapy instead of either in-person observation at the clinic or by a community health worker visiting the participant. As observing patients taking TB medicines is the recommended practice, due to the difficulties of patients adhering to the standard of care treatments, this adjustment reduced the burden of participating in the study and could be utilized to keep trials moving forward in suboptimal conditions in the future.

4. Identify the risks early and figure out the mitigation strategies in advance.

In many ways, this is a universal requirement that clinical trials in HICs must follow as well. The difference is that in those settings, the mitigation strategies are less frequently deployed as the situations tend to be more stable.

For example, in HICs we always made sure that trial sites had backup generator capacity, but they were not commonly used. In contrast, many of our LMIC trial sites deploy their generators much more often due to rolling blackouts or instability in the power grid.

With investigational products, almost all of which have storage temperature requirements — from 2 to 8 degrees C, for example — we often split product storage into two refrigerators, make sure that backup generators are available, and encourage additional backup (such as solar panels). Our clinical operations and clinical supply staff closely monitor investigational product storage and trial enrollment when using regional depots (as opposed to depots that are in the country) or in cases of rapid enrollment (for certain vaccine trials, enrollment and participation can proceed quickly) to ensure the site’s demand for investigational products is met.

Additionally, evolving data privacy regulations require the registration of our organization in different jurisdictions. Many countries in a current Phase 3 trial have been implementing these regulations, and we must collaborate closely with our colleagues in compliance and risk management to communicate timelines, utilize their understanding of the evolving landscape, and work closely with local legal services to ensure our trials are appropriately registered.

5. Leverage geospatial insights.

This data, which includes any details that can be placed on a map — from population density estimates to healthcare facilities and transportation infrastructure — can support country and site selection and also can inform the entire enrollment process.

We always want to work with trial sites where the most patients are located but sometimes it can be difficult to determine where there is a sufficient level of incidence or prevalence of the disease. Many settings do not have electronic medical records that can be queried to identify pockets of potential participants.

We have applied geospatial research in a number of trials now, tackling malaria, nutrition, and tuberculosis. Spatially derived contextual and epidemiological metrics are utilized in conjunction with other operational information such as locations of labs or clinical supply depots to identify areas that are optimal for the selection of clinical trial sites. Additionally, this allows us to set site-specific participant enrollment targets based on the characteristics of their catchment areas. Finally, geospatial tracking systems are used for nearly real-time monitoring of clinical trial activities.

These five guidelines help us provide the backbone for the clinical operations work that determines whether the trials will be successfully operationalized. The efforts bring us into collaborations with clinicians and researchers who all have a passion for serving their communities. Our clinical operations team not only enables the research that they conduct on behalf of the Gates MRI, but we support their work in building a sustainable clinical trial infrastructure and ensuring that all stakeholders benefit as we help find solutions to the most pressing global health issues.

About The Author:

As the head of clinical operations at the Bill & Melinda Gates Medical Research Institute, Caitlin Ciavarro ensures the successful execution of clinical trials that advance global health initiatives, directly contributing to the development of transformative medical solutions for underserved populations worldwide. With over 20 years of experience in clinical operations, Ciavarro has led teams at Gates MRI, Sanofi Genzyme, GSK, and Novartis. Her expertise spans from early-phase trials to large-scale global programs, including vaccines and rare diseases. Ciavarro is known for driving innovation, building high-performing teams, and fostering a strong quality culture in clinical trial execution.