Latin America as a Key Driver for Global Success: Opportunities and Challenges Against the Global Clinical Research Backdrop

Abstract

Moving Clinical Development to emerging countries could provide advantages to R&D companies. The availability of trial- naïve patients and often treatment-naïve patients together with less competition for enrollment, high quality of investigators and lower costs, are considered key factors for this decision. Nevertheless a clear knowledge of local regulatory processes, understanding of cultural differences and operational particularities are needed to optimize the result of this move. In this article we analyze the Latin American environment for Clinical Research focusing on the regulatory and ethical framework and the challenges and issues that can be found in the Region.

Introduction

In the last 10 years there has been an increasing participation of emerging countries in pharmaceutical development projects. The conduct of clinical studies in different development phases in these regions has been driven by the need to expedite development timelines, holding down costs without affecting quality standards. Moving to emerging countries has allowed access to a large pool of “trial-naïve” and often “treatmentnaive” patients in settings where competition for patient enrollment is lower.

Among the challenges faced by companies addressing the strategic decision to implement part of their clinical development in new countries and regions, there is the need to know local regulatory processes, to understand the particular cultural aspects of interpersonal physicianpatient relationships, and to adjust global processes and systems so that they can be appropriately applied within these new environments.

Some authors have tried to define the “attractability” of emerging countries by reviewing the different factors which influence the feasibility of R&D projects. For such purpose, they take into account the availability of patients, the cost of medical procedures and fees, regulatory conditions, the expertise of human resources available and infrastructure. By assigning a value to each one of these factors, a comparative score is reached by which countries in the region are among those ranked in the first places [1].

From the economic viewpoint, though in many cases regular health care costs in emerging countries are lower than in Europe and North America, the greatest opportunities to maximize resources invested in these projects are attributed to lower costs of support services and diagnostic procedures. On the other hand, medical communities receiving these projects obtain and notice clear benefits from this activity, such as the creation of positive relationships among investigators globally, the cooperation in answering relevant scientific questions, the transference of knowledge and technologies and the improvement in clinical practice with the introduction of quality systems and good clinical practices. However, efforts should be maximized so as to prevent exposing research subjects to an unnecessary risk by including them in studies conducted under substandard conditions, since the high interest and spreading of this activity may lead to more professionals willing to engage in research without having the necessary qualifications and experience.

Latin America and its Increasing Role in Global Clinical Research

Latin America is home to almost 600 million inhabitants, with a mostly stable political and economic environment.

Brazil faced the global economic crisis effectively, achieving a faster recovery as compared to many developed countries. Argentina is also in the process of overcoming crisis and has recovered annual growth rates close to 9%.

Though in the region a marked social and economic inequality can still be noticed [2,3], over the last years there has been a growth in middle classes and a stronger focus on educational and health policies, accompanied by a growth in health care infrastructure and life expectancy.

In the region, average life expectancy has almost reached 75 years, the urban population is close to 80% and the average literacy rate is of 90%.

Another typical feature of the region is that six countries (Brazil, Mexico, Colombia, Argentina, Peru and Chile) concentrate 80% of the population (equivalent to that of 25 EU member states) speaking only two languages within a setting which favors the development of applied research.

Latin America has a well-developed pharmaceutical market and a population exhibiting a particular epidemiological profile, though prevalence of risk factors and diseases is similar to that prevailing in EU or the US.

For all these reasons, in addition to the regional increase in personnel engaged in research activities within the pharmaceutical companies, there has been a substantial development of the activities of CROs (Contract Research Organization) which, though they have their regional “hubs” in Argentina, Brazil or Mexico, they provide their services across all countries in the region.

Presently, a significant percentage of global clinical studies are being conducted in Latin America. Sites in Brazil, Mexico and Argentina are participating in over 1000 global studies, and the participation rate has been steadily increasing in the past 5 years, exceeding 6% of the clinical trial activities documented in international registries.[4]

These countries have a health care and clinical trial management infrastructure which allows to foresee a steady growth in terms of quantity, complexity and quality of projects in the short and medium term. In the framework of emerging regions, countries in Latin America offer some structural and cultural advantages which favor the conduct of clinical studies: a traditional close relationship between health care providers and their patients, a well-developed public and private hospital infrastructure in urban centers of over one million inhabitants, with a highly qualified medical community trained as per European and US standards.

In addition, at the present time these health care providers are willing to participate in global scientific and academic activities.

The experience gained by international companies that have already conducted part of their molecule development in countries of the region during the past 10 or 15 years strengthens their interest in continued investment.

In general, saturation of research sites is very low when compared to other regions[5], but it is substantial in some institutions where many clinical studies have been conducted in the last years. This poses an additional challenge to the sponsors: to bet on the challenge of incorporating new sites and new research staff able to provide valid data and take good care of patients participating in the studies.

Therefore, it is encouraging to notice a substantial growth in training based on ICH-GCP standards targeted to the site personnel involved in clinical research activities (e.g., investigators, study coordinators, nurses, members of the Sponsors’ teams, members of regulatory agencies and members of the Ethics Committees).

There are certain factors which should be taken into account when deciding to initiate a development program in Latin American countries:

• Regulatory Complexity: The increase in the activity over the last 10 years has naturally led Health Authorities of Latin American countries to implement, where not available, legal instruments aimed at regulating clinical research. In those countries with regulations in place, some have been amended and tailored to the new environment. Though the publication of the “Documento de las Americas”[6] in 2005 was an attempt at a regional harmonization guideline to be incorporated to the legislation of the different countries, each country has developed its own specific regulations. In some countries, the different provinces or jurisdictions have also drawn up and published regulations aimed at controlling the activity in their territories, this often implying multiple overlapping formalities, thus resulting in the extension of regulatory timelines within the same country.

But, though regulatory requirements are varied, they are not slack. Much to the contrary, regulatory frameworks impose clear requirements intended to protect populations voluntarily participating in clinical studies.

• Extended Regulatory Review Timelines: The review of each clinical study protocol by regulatory agencies is thorough and comprehensive. The members of the regulatory agencies and Ethics Committees in Latin America are deeply concerned about preventing patients from being exposed to unnecessary risks during the study, or being treated unfairly as compared to volunteers from developed countries. Other concerns are the implementation of practices which might harm the basic principles of justice, autonomy and beneficence or ignore the preferences or mores of those communities where research projects are conducted. It is worthwhile commenting that regulatory agencies take their role in the protection of the clinical study population very seriously. Andthough the attitude towards clinical research has been influenced by ideological prejudices, we are currently witnessing a positive mind-set with a rational and committed approach in almost all countries of the region.

Figure 1- Start-up timelines – Comparative overview

• Extended “Start-up” Timelines: Bureaucratic red tape subsequent to the evaluation itself and related with the import of materials used in clinical trials, is complex. This often forces sponsors to involve themselves personally because of the impossibility of delivering the study drug and supplies directly to the sites, and calls for a careful preparation of shipping documents and bills of entry covering study materials in order to avoid additional delays. When added to the evaluation timelines, this makes the time periods required to start incorporating study sites extend beyond those required in other regions. Figure 1 shows a comparative overview of average range start-up times in LA countries according to data collected from different projects and sponsors.

The high level of training and the willingness of investigators and their research staffs allow for a swift and sustained enrollment of patients in the studies once the sites have been activated.

Ethical Evaluation of Research Projects in Latin America

There is an ever increasing scrutiny of research activities, either independent or sponsored by the pharmaceutical industry, on the part of organizations concerned with patients’ rights[7-10]. The new legislations promote certification and a higher level of professionalism of Research Ethics Committees, calling for a binding “ethics monitoring” of studies by such committees.

Some of the aspects raising concern that are focused during evaluation are: study design (e.g., use of placebo, number and frequency of biological samplings, etc.), financial agreements between parties, the implementation of liability insurance covering potential damages to study participants, the supply of comparators or backbone therapies, the supply of standard therapies (or even of study drug if satisfactory results have been achieved) after completing study, appropriate and complete flow of safety information about the research drug throughout the study, the appropriateness of conducting genetic studies and research conducted in vulnerable populations.

An aspect to be especially considered is native populations. About 40 million people in Latin America come from pre-Columbian native communities. Their cultural particularities, poor command of Spanish or Portuguese and their ancestral traditions (e.g., the regular use of herbal medicines or the possibility of subordinating their personal choices to the will of a community leader) turn them into a particularly vulnerable group. The involvement in research activities of these communities as such should be thoroughly assessed by Ethics Committees and reserved for duly justified cases.

Conclusions

Among emerging markets, Latin America has become an attractive place to conduct clinical studies for a number of reasons, especially because of the possibility of getting access to a large population of potential patients, treated by qualified health care professionals, enthusiastic about the activity, in a region distinguished by an increasingly robust regulatory framework and ethical surveillance.

Latin American investigators are willing to cooperate with sponsors and health authorities in discussing with the Ethics Committees or regulatory agencies those protocol aspects which might be a source of concern for evaluators, as well as to abide by their decisions and recommendations.

The possibility of handling documentation in only two languages and cover a huge population, adds a distinctive advantage to the region, bearing in mind the mandatory nature of translating regulatory documents and considering the subtle colloquial and formal linguistic differences among Spanish-speaking countries in the region.

Since a large portion of the Latin American patient population is particularly vulnerable for economic, educational and social reasons, sponsors and investigators should commit with the efforts made by government agencies and non-governmental organizations to protect the personal rights of these patients and their communities.

It should be taken into account that part of the population of the region often faces the dilemma of having to participate in a clinical study as the best or only way to gain access to modern and potentially beneficial medical care.

The success in conducting clinical studies in a promising region such as Latin America is, therefore, the result of an efficient and respectful coordination of the needs of sponsors, ethical and regulatory bodies and investigators.

References

1. Bailey W., Cruickshank C., Sharma N. Make your move: Taking clinical trials to the best location. Executive Agenda. 2006;1:56-62.
2. López-Calva L.F., Soloaga I. et al. UNDP. Regional Human Development Report for Latin America and the Caribbean 2010. Available at http://www.idhalc-actuarsobreelfuturo.org/site/engl/index.php Accessed on February 24th 2011.
3. Mora Salas, M., Pérez Sáinz J.P., Cortés F.. Desigualdad social en América Latina, viejos problemas, nuevos debates. San José, FLACSO, 2004.
4. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/
5. Hurley D., Lipezker M., Melgar H., Mazzolenis D. Latin America Clinical Trial Authorizations. Overview and update. Regulatory Focus. 2009;38-42.
   
6. Good Clinical Practices: Document of the Americas. Available at: http://www.paho.org/english/ad/ths/ev/GCP-Eng-doct.pdf. Accessed on February 24th 2011.
7. Glickman S.W. et al. Ethical and Scientific Implications of the Globalization of Clinical Research. N Engl J Med 2009; 360:816- 823.
   
8. DeMaria A.N. The Exportation of Clinical Research. J Am Coll Cardiol 2009;53;1919-1920.
   
9. Fitzgerald D.W.. Comprehension during informed consent in a less-developed country. Lancet 2002; 360: 1301–02.
10. Loue S.. A consideration of ethical and legal issues in multi-site studies. Acta Bioethica 2004; 1: 69-73.