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Coffee with the ExpertThe importance of clinical development in low-and-middle income countries

The importance of clinical development in low-and-middle income countries

Lessons from Latin America with Dr. Xavier Saez Llorens

Authors:
Javier Casellas, M.D., Ph.D.
Enrique Chacon-Cruz, M.D., MSc
Felicitas Colombo, MPA

Pediatrician and infectious disease specialist Dr. Xavier Saez Llorens serves as the Chief of Infectious Diseases and the Director of Clinical Research at the Dr. José Renán Esquivel Children’s Hospital in Panama. He has been a member of the National Committee of Bioethics in Research (NCBR) for the past 10 years and is recognized as a Distinguished Researcher in the National Research System (SNI, Senacyt) and at the Vaccine Research Center, Cevaxin. 

Most recently, he received special recognition as a Latin American vaccine researcher at the Global Health Conference of the Americas (September 2024) from Florida International University. He also received a Principal Investigator (PI) award for his outstanding contributions to the M5-ABMG study in support of the Global Polio Eradication Initiative, presented by the Global Health Technologies Coalition (GHTC) Impact Awards (December 2024).

Dr. Saez-Llorens earned his medical degree from the Faculty of Medicine at the University of Panama. He completed his doctoral training in Pediatrics (CSS, Panama) and postdoctoral training in Infectious Diseases at UT Southwestern Medical Center in Dallas, Texas.

Throughout his medical career, Dr. Saez-Llorens has received multiple awards for his research and publications in childhood infections. Notably, he was recognized in Chicago as one of the best young researchers in the United States in the field of infectious diseases (ICAAC 1991). He also received the award for having the highest number of publications in international scientific journals among Panamanian physicians (Senacyt 2013), the William Gorgas Medal for his outstanding contributions to vaccination and public health (Gorgas Institute 2017), and the award for excellence in scientific research from the Association for the Advancement of Science of Panama (APANAC 2021).

Dr. Saez-Llorens is an active member of the Pediatric and Pediatric Infectious Diseases Societies in the United States, Latin America, and Spain. He is a member of the Catalan Institute of Biological Sciences, the National Bioethics Committee, and served as a consultant for the Ministry of Health of Panama in the fight against the COVID-19 pandemic, focusing on vaccination efforts.

Demonstrating his commitment to research, Dr. Saez-Llorens is the principal investigator of numerous international clinical trials supported by the Bill & Melinda Gates Foundation, the National Institutes of Health (NIH), and various academic institutions and pharmaceutical companies.

Clinical Research in Latin America: now and then

Dr. Saez-Llorens has been involved in vaccine clinical research for nearly 20 years. The significant impact of conjugated vaccines against bacterial meningitis inspired his commitment to vaccine clinical development. He recalls the lack of awareness regarding quality local research among potential volunteers, the weak regulatory frameworks for ethical processes aimed at protecting human rights, and the challenges in implementing adequate protocols for experimental drugs and vaccines.

“At the beginning in Panama, there was a lack of experienced staff in performing clinical trials, an absence of dedicated units to do research outside hospitals for conducting studies in healthy people. So, those were relevant obstacles to proper research activities in my country. And I remember that in those days, we started the very challenging study of a new pneumococcal vaccine, PCV10. It was called later Synflorix,” comments Dr. Saez-Llorens.

The ethical issues faced by investigators, combined with intense commercial competition among vaccine manufacturers and widespread misinformation from tabloid press, complicated recruitment, data capture, participant retention, and overall trial execution. Dr. Saez-Llorens believes the situation has improved substantially in Panama and possibly in other Latin American countries as well.

For example, Cevaxin, a clinical trial center in Panama, has developed a public-private model with key partners to enhance clinical research as a valuable care option for volunteers. Guided by the extensive clinical research experience of Dr. Saez-Llorens, this model addresses many barriers to effective participation in vaccine trials. Key features include expanded access to healthcare through patient-centric approaches, high-quality care, and rigorous ethical standards that promote patient satisfaction and build trust.

“We underscored the importance of solving main worries of participants. For example, doubts about taking a chance with their health, concerns about the risk of clinical research not being treated as a focus of drug industry merely, involving subjects [in the research process journey], regular healthcare providers, and making subjects feel that they are being treated like valued individuals. In addition, we have engaged the participants in the study design process, asking about their insights on the outcomes of most relevance to them,” he explains.

Examples of participant engagement include conducting lab tests, sharing study results, utilizing digital applications for frequent communication, and providing home-based visits. We also seek volunteers’ input on how to facilitate their participation, including visit scheduling, locations, and data collection methods, employing all available technology to ensure that patients feel they are benefiting from the research.

“Finally, and it’s very important, not only in Panama but also in Latin America, we have put all our efforts to eliminate the historic concept of guinea pigs, stressing the critical role of modern ethical committees and comprehensive consent processes to ensure protection of human rights and respect of people’s autonomy in their own informed decisions,” he concludes.

Roadblocks in Latin America

According to Dr. Saez-Llorens, the primary roadblocks in clinical research in Latin America are related to regulatory requirements for pediatric studies. These regulations are often more stringent than those for adult trials, necessitating extensive preclinical data and longer approval timelines. Additionally, recruiting pediatric participants is challenging due to parental concerns, increasing vaccine hesitancy, the requirements for informed consent forms (ICFs)- which often requires signatures from both parents in some countries – and various logistical barriers.

“But I think we have to improve the understanding that we need a robust regulation end-to-end, including research laws, and we have to have properly trained staff, not only in conducting clinical studies in methodology of research, but also in bioethics and technical aspects for vaccine development,” he points out.

Solid ethical committees are crucial, especially when conducting research involving infants, children, and pregnant women. It is vital to engage these groups in research to prevent them from becoming therapeutic orphans.

Dr. Saez-Llorens also emphasizes the need for competitive timelines to attract investment from pharmaceutical companies and philanthropic organizations in Latin America. This includes having qualified, fully dedicated personnel trained in Good Clinical Practices (GCPs) and clinical methodologies that facilitate adequate recruitment and retention. Overcoming these obstacles relies on trained professionals with strong communication skills, capable of engaging not only with participants but also with the media and health authorities.

Panama serves as a success story, having developed research units that simulate public-private models for conducting studies. This approach has enhanced their reputation and opened doors to publishing in prestigious international journals. Cevaxin’s credibility is further bolstered by its high enrollment rates and successful participant recruitment, achieving four successful inspections by the Food and Drug Administration (FDA), one by the European Medicines Agency (EMA), and by several international independent research auditing companies.

Other regions, such as Africa and the Asia-Pacific, that face similar limitations could benefit from the experiences of Latin America. This model could facilitate investment in local science and clinical trials. However, the challenge remains: how can we convey the importance of conducting local research and clinical trials?

“I think every region in the world, they have to work for doing innovation and research in their places. That’s a way to improve the situation in the world, in many regions,” asserts Dr. Saez-Llorens. “The things that happen in Africa, in a very remote place in Africa, can affect the people in the U.S. or in Europe. So this is a globalized planet.”

In his view, science is crucial for the progress and independence of nations. During the pandemic, many countries relied heavily on imported essential public health products, not just vaccines. Dr. Saez-Llorens contends that true prevention requires not only investment in clinical trials but also in basic science.

“In science in general, clinical is only a part of the research. Also in basic science and also in social sciences, epidemiology sciences. So we need to invest in all the aspects of science in every part of the world, not only in a few places,” he emphazises.

Clinical Research and National Immunization Program inclusion of vaccines

A critical question is how clinical research in Latin America impacts the decision-making process for vaccine implementation. Before the year 2000, there was an average delay of almost six years between the approval of vaccines in Latin America and in industrialized countries. However, after 2000, as Latin America began conducting local research, this dynamic changed dramatically. It allowed the medical community and health authorities to better understand the burden of disease, as well as the safety and efficacy of vaccines within their own populations.

“For example, a vaccine that is just studied here in Panama or in several Latin American places goes to the national immunization scheme very fast. Even simultaneously with the moment in industrialized countries, or even before. For example, the rotavirus vaccine was approved in Brazil and in Panama before the U.S. and Europe. So I think that doing research locally helps on the rapid approval, the rapid incorporation of good vaccines in our national immunization programs,” points out Dr. Saez-Llorens.

Latin America & manufacturing capacity

During the COVID-19 pandemic, Latin America faced significant challenges in vaccine procurement, leading to delays, increased costs, and difficult choices between quality and price. The notion that manufacturing sites in Latin America and other developing countries can provide faster access to vaccines at a lower cost is not new. 

In the aftermath of the pandemic, several countries in the region began launching initiatives to establish manufacturing plants, facilitate technology transfer, and develop vaccines and monoclonal antibodies. These efforts will be crucial for managing future epidemics and ensuring adequate supply among countries in the region. However, for these initiatives to be effective, they must be sustainable and supported by regional agreements to avoid duplication of efforts and to maximize capabilities.

“To me, the key problem has been mainly in terms of sustainability. Because some countries beyond Brazil, for example, Argentina, Colombia, Mexico, Cuba, have had previous experience on vaccine manufacturing. But these initiatives lost public funding over time. So sustainability is a very important issue in that regard,” asserted Dr. Saez-Llorens, who firmly believes that we must be prepared for the next pandemic.

The ideal trial design

As a principal investigator (PI), Dr. Saez-Llorens has observed that many trial protocols require adjustments to ensure feasibility. In his experience, an ideal vaccine trial design would be a randomized, blinded, controlled study with clearly defined objectives that evaluate clinical immunological and efficacy endpoints, optimal dosing schedules, and strategies to ensure rapid yet sustained protection from disease.

Key features of such trials include ethical considerations that clearly communicate the benefits and risks to participants, an adequate sample size, well-defined endpoints, and continuous safety monitoring by an independent Data Safety Monitoring Board (DSMB). High retention rates for follow-up visits are also essential. Dr. Saez-Llorens believes that adaptive designs have optimized resource use for these studies, many of which have been conducted in Panama for dengue, polio, rotavirus, COVID-19, and monoclonal antibodies against RSV.

“Some good examples, for example, of vaccine trials in our region have been the rotavirus efficacy and safety trials developed in Latin America. Also the dengue vaccine trials, which included long-term safety and efficacy,” he recalls. He also notes the current RSV studies that have enabled the real-time incorporation of preventive strategies worldwide.

The recruitment funnel problem

The patient recruitment process can be visualized as a funnel that channels patients into clinical trials while determining their suitability for participation. While the combined Latin American clinical trials market was estimated at USD 2.17 billion in 2024, and is projected to reach USD 4.08 billion by 2030, a significant percentage of potential patients are lost before enrollment.

“Yes, that has been a huge problem in the past. But nowadays, I think we have techniques or strategies to retain the subjects during the last very long trials. For example, in dengue, the WHO and FDA told us that we needed to have at least a five-year follow-up for dengue to be sure that the vaccine was safe and not replicate the previous phenomenon that had been viewed with the first dengue vaccine,” states Dr. Saez-Llorens, who proudly notes that their retention rate exceeded 90% after five years.

With a team of highly qualified professionals in Good Clinical Practices (GCPs) and dedicated personnel for the dengue trials, their recruitment and retention units maintain strong communication with subjects while also providing incentives.

“In Cevaxin [trials], for example, what we have done is we give to them all the vaccines that are included in the national program when they participate in the study. We also have, in pediatric study, we have pediatricians that are involved in growth and development, in giving instructions about maternal milk, and also solving many of the health problems, not only of the participants, but also of the families of the participants,” reveals Dr. Saez-Llorens, whose team also collaborates closely with peripheral health centers and hospitals, ensuring active participation from pediatricians who are on call 24/7.

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