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Trials and Tribulations: Running Clinical Trials in LMICs Can Be a Challenge

January 24, 2024

February 2024

Mary Ellen Schneider

Mary Ellen Schneider is a medical journalist based in Setauket, New York.

Ezintsha conducts community-based participant recruitment for a study of COVID-19 therapeutics.
Ezintsha conducts community-based participant recruitment for
a study of COVID-19 therapeutics. Photo courtesy of Ezintsha.

The need for greater diversity in clinical trials and a growing understanding that there are large untreated patient communities in low- and middle-income countries (LMICs) are driving interest in conducting trials in these traditionally overlooked locations; however, a lack of research infrastructure, trained staff, and local governmental support is hampering efforts to expand trials to LMICs.

While more than 75% of the world’s population lives in LMICs, randomized controlled trials (RCTs) conducted in these countries make up just 32% of all RCTs registered with the World Health Organization (WHO). Certain heavily populated regions, such as south Asia and sub-Saharan Africa, are especially underrepresented in that total. Just 5% of RCTs are conducted in south Asia, and 2% are conducted in sub-Saharan Africa, according to 2019 data from the WHO International Clinical Trial Registry.1,2

“LMICs are underutilized in clinical trials, but the numbers are steadily growing,” said Nkuli Mashabane, BPharm, MBL, director of research operations for Ezintsha, a division of Wits Health Consortium at the University Witwatersrand in Johannesburg, South Africa. “You can’t conduct a study purely in the U.S. and think those results are generalizable to LMICs. I think the industry has realized that if you’re conducting a study on a drug you intend to have used by everyone around the world, then the research must be done in those countries as well.”

More Patients, More Disease

The volume of clinical trials across LMICs is variable. Countries like Brazil, Argentina, and Egypt are conducting more trials than Europe and Canada, while countries in sub-Saharan Africa are often underused, said Edward J. Mills, PhD, a clinical trialist and professor of health research methods, evidence, and impact at McMaster University in Ontario and at the University of Rwanda.

LMICs have several benefits for trial sponsors, he said, such as lower costs, higher numbers of patients who can be accrued to the trial, high rates of incidence of disease, and a higher rate of untreated disease. “If you are trying to run a trial, even for a disease relevant to North America, you are going to get people who tend to be sicker and have more clinical outcomes [in LMICs],” Dr. Mills said.

For instance, patients in an LMIC who participate in an oncology trial are not likely to have received previous treatment, allowing researchers to use death, rather than disease progression, as a trial outcome. “From a trial conduct point of view, low-income countries are going to be much better for the validity of your trial,” he said.

Ms. Mashabane, who has been working on clinical trials in Africa for nearly 20 years, said local research organizations like hers have developed clinical research expertise and participant-centric approaches over the years. This allows them to accrue study participants more efficiently and retain them at a high level, making the organizations attractive partners for companies and researchers in high-income countries looking to expand their studies.

However, the U.S. Food and Drug Administration (FDA) has been a stumbling block to conducting more trials in LMICs because it encourages trial sponsors seeking drug approval in the U.S. to enroll patients who reflect the American population, which often means patients who have had prior lines of treatment, Dr. Mills said. That makes countries like Brazil — which has more patients who fit those criteria, along with a highly skilled workforce — an attractive trial location for industry-sponsored drug trials, he added.

Research Barriers

Conducting trials in LMICs can be challenging because of variations in local research infrastructure and governance issues. A 2021 scoping review of original studies detailing barriers and facilitators to critical care research conducted in LMICs outlined several potential obstacles, including limited local funding for research, limited local research staff and lack of mentors, too much or too little regulatory oversight, lack of dedicated research time, and limited lab equipment and technology.1

Raúl Córdoba, MD, PhD
Raúl Córdoba, MD, PhD

One of the fundamental differences between conducting research in high-income countries like the U.S. and LMICs is the lack of government funding for research, said Raúl Córdoba, MD, PhD, an attending hematologist and coordinator of the lymphoma unit at Fundación Jiménez Díaz University Hospital in Madrid. In the U.S., the National Institutes of Health provides significant funding to conduct non-industry-sponsored trials, which allows researchers to explore relevant clinical questions that are not directly related to the efficacy and safety of a specific drug product. But LMICs typically don’t have that type of robust funding and focus public health resources on other issues, he said.

“If they have to deal with public health issues, for example, they’re not going to focus on a specific subtype of cancer because they have other needs,” said Dr. Córdoba, who also serves on the American Society of Hematology’s (ASH) International Members Committee.

Protected research time is another significant hurdle, said Surbhi Grover, MD, MPH, an associate professor of radiation oncology and director of Global Radiation Oncology at the University of Pennsylvania (UPenn). She is also the oncology lead for the Botswana-UPenn Partnership and an adjunct senior lecturer at the University of Botswana.

The National Institute of Biomedical Research in Kinshasa, Democratic Republic of the Congo. Photo by Dr. Jamie Forrest
The National Institute of Biomedical Research in Kinshasa,
Democratic Republic of the Congo.
Photo by Dr. Jamie Forrest. 

“Researchers in LMICs are already overwhelmed. Even if you try to buy down their time with a grant, it’s very hard to get protected time to focus on research,” she said.

When funding is available to train local researchers, there is often not sufficient personnel to cover their patient care responsibilities. If they can leave their day-to-day job for training, their position may not be guaranteed when they return, she said.

Cancer trials come with added layers of complexity because they involve pathology, staging, and imaging before treatment can even begin. Trials that include radiation and surgery have additional protocols and capacity needs, Dr. Grover said. “Where we get stuck is that this initial work and infrastructure is a big lift,” she said. “It’s the same challenge you have [with] proper access to care.”

The limited research infrastructure often means researchers in LMICs are likely to lack access to quality assurance monitors, which can in turn create doubts about the veracity of the data, said Ivan Kiggundu Mambule, MBChB, the project lead for the Cabotegravir and Rilpivirine Efficacy and Safety (CARES) trial in Kampala, Uganda.

But Dr. Mills, who has been conducting trials in Africa for decades, said the biggest barrier is simply a lack of familiarity and a certain amount of inertia within the research community. “Pharmaceutical companies, on average, don’t do their own trials. They hand it over to contract research organizations, and then those contract research organizations tend to go to sites they already have,” he said. “So, the vast majority of them will be in the Western world or the global North, and much less in the global South.”

Overcoming Challenges Through Partnerships

Some of the work to overcome these challenges is already underway. ASH’s International Members Committee has a program designed to build research expertise and capacity in LMICs by bringing researchers from these countries to the U.S. for training and mentorship. Through the Visitor Training Program (VTP), ASH provides funding for hematologists and hematology-related health care professionals in LMICs to receive training on a specific topic or technique for up to 12 weeks. The training is provided in the clinic or lab of an ASH member who also mentors the LMIC researcher.3

Inside an Ezintsha mobile clinic in Johannesburg, South Africa.   Photo by Dr. Jamie Forrest
Inside an Ezintsha mobile clinic in Johannesburg, South Africa.
Photo by Dr. Jamie Forrest.

The VTP, which was launched in 2008, covers the cost of visa fees, airfare, accommodations, and daily living expenses during the training. Applications are accepted each year with the goal of bringing hematology research skills back to local communities, Dr. Córdoba said.

ASH also provides training on-site in Latin America for researchers who cannot travel to the U.S. but need support building local research capacity. The Clinical Research Training Institute in Latin America is a two-day workshop that is available to fellows and early- to mid-career hematology faculty in Latin American countries who are seeking to gain experience designing and carrying out clinical trials. The program includes training on methodologies for patient-oriented research, individualized mentorship, and networking opportunities. Additionally, participants can develop a capstone project based on skills gained through the workshop.4

This type of training and mentoring is critical for raising standards in LMICs, said Dr. Mambule. Training in more advantaged institutions helps researchers with individual projects but also gives them the skills to mentor colleagues in their home institutions, he said.

Another key strategy for accelerating the establishment of trials in LMICs is engagement with local governments, Dr. Grover said. Local leaders need to be educated on the fact that building up research infrastructure directly translates into providing access to evidence-based care, she said. Dr. Grover recommended that professional societies and researchers from high-income countries work with governments in LMICs to identify a group of local researchers who could be trained in research methods and begin with small projects, such as prospective cohort studies, before transitioning to trials with pragmatic designs.

“The trial structure that exists in North America just wouldn’t work here, so you need to be a little more pragmatic,” Dr. Grover said.

Ms. Mashabane said it is important not to make assumptions about the level of research expertise in LMICs because they are not all the same. At her institution, they work on many global trials, and outside researchers are often shocked by the available equipment and staff expertise, she said.

“We need to start by dispelling the myth that these counterparts on the other end of the earth don’t exist,” she said. “They do exist, and the collaborations could make life so much easier for all of us. We probably have more in common than we think we do, and we probably could serve each other’s interests better, making a more meaningful global impact if we just started talking.”

Ethical Considerations

As clinical trials expand in LMICs, considerations about local needs are paramount, experts said. A recent analysis of trials being conducted in Latin America and the Caribbean showed that progress in aligning clinical trials with the health needs of LMICs has been mixed. The study examined data from the WHO International Clinical Trial Registry and found that the diseases most studied in trials — diabetes, asthma, and cancer — create significant disease burdens in these areas. However, critical transmissible diseases like AIDS and tuberculosis are being understudied in these countries.5

One of the major ethical principles of conducting drug trials in LMICs is that companies should make those therapies available in those countries after approval. Although that is the goal, there is often a long gap between when drugs become available in high-income countries and LMICs, and some drugs do not get marketed in LMICs at all, Dr. Mills said, but researchers can still provide a benefit to LMICs by building research capacity and leaving behind expertise.

“Are you going to mentor staff and employ staff so there is now a new cadre of health workers who weren’t there before?” Dr. Mills said. “That tends to be just as acceptable as access to drugs afterwards. There’s a tremendous thirst for the intellectual capacity for conducting clinical research that they know will lead to intellectual innovation.”

All trials in LMICs must consider that there are vulnerable patients in these regions. For instance, if a patient can only gain access to life-saving treatment by participating in a clinical trial, then researchers must ensure that participation is truly voluntary, Dr. Córdoba said. Additionally, health literacy may be at lower levels than in high-income countries, and informed consent documents and discussions need to be adjusted to account for those differences and enable patients to ask questions and understand risks, he said.

Work to overcome barriers to research in LMICs must continue because it is not an option to leave these regions out of clinical trials, Dr. Grover said.

“Building clinical trials capacity in LMICs is not even an issue to be discussed because this is where the cancers are going to be,” she said. “There’s differing biology, differing metabolism of drugs, and different challenges in management in these areas. Unless patients from different places are included, where the diseases are, we won’t know the implementation challenges for particular drugs.”

References

  1. Tirupakuzhi Vijayaraghavan BK, Gupta E, Ramakrishnan N, et al. Barriers and facilitators to the conduct of critical care research in low and lower-middle income countries: a scoping review. PLoS One. 2022;17(5):e0266836.
  2. Park JJH, Grais RF, Taljaard M, et al. Urgently seeking efficiency and sustainability of clinical trials in global health. Lancet Glob Health. 2021;9(5):e681-e690.
  3. American Society of Hematology. Visitor Training Program. Accessed September. 25, 2023. https://www.hematology.org/awards/career-enhancement-and-training/visitor-training-program .
  4. American Society of Hematology. CRTI in Latin America. Accessed September. 25, 2023. https://www.hematology.org/awards/career-enhancement-and-training/clinical-research-training-institute-latin-america.
  5. da Silva RE, Amato AA, Guilhem DB, et al. International clinical trials in Latin American and Caribbean countries: research and development to meet local health needs. Front Pharmacol. 2018;8:961.

 

 

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