Trials in Latin America

One of today's most important emerging regions for clinical trials is Latin America, which is being increasingly considered for trials because it offers significant potential.

Regulatory enforcement bodies, quality investigators, ethics committees ensuring patient safety, proactive Good Clinical Practice (GCP) policy development, and huge research naïve populations have been cited as contributing to Latin America's explosive growth.¹ Yet, as in many regions, important challenges remain, including language and cultural barriers.

Fertile ground

Regardless in what country or region a clinical trial is conducted, successful trials can be determined by a number of factors, including:

• Experienced and efficient investigational teams

• The presence of a target patient population willing to participate in trials

• Epidemiologic considerations around disease and prior treatments

• Updated regulations in conjunction with adequate approval timelines (see sidebar)

• The health system and overall standard of care

• Ethical committees, which work for the safety and respect of participant patients

Regulatory Practices

So why has Latin America become such a hotbed of clinical trial activity? Many Latin American countries possess each of these success factors, which we'll discuss.

Investigational teams

One of the most important factors in conducting a successful trial is the quality and enthusiasm of the investigators. Because clinical trials are relatively new in Latin America—within the past 20 to 30 years—investigators tend to treat participation as more novel and interesting than their counterparts in other countries where trials have been occurring for a longer period of time. Many of these investigators place a high value on the scientific and academic aspects of the trial, and are pleased when they are invited to participate.

However, don't mistake enthusiasm or novelty for inexperience. As Latin America became recognized for its enrollment potential and the high quality of the data obtained, the number of clinical trials started in the three largest countries in the region increased significantly over the past five years. For example, the number of clinical trials started in Brazil has increased 58% (from 153 in 2005 to 241 by 2009). In Argentina, the growth in new trial starts is more modest at 16% (from 97 to 112 over the same period), while Mexico has achieved a 49% increase in new trial starts (from 106 to 158 over the same period).²

This growth, combined with other factors, has led to the proliferation of educational forums where investigators are schooled in all aspects of clinical research. For example, in Argentina courses are offered at the Instituto de Biología y Medicina Experimental, Universidad Austral, and Fundación de Estudios Farmacológicos y de Medicamentos.³ In Brazil, courses are frequently offered by the Brazilian Society of Pharmaceutical Medicine and the Brazilian Society of Clinical Trials. Many Latin American countries require that investigators, study coordinators, and nurses take certain courses. Certification is planned to be requested by some regulatory authorities, such as the Argentina Ministry of Health, for physicians proposed as principal investigators.⁴

Patients and epidemiology

An advantage of Latin America is that it has densely populated areas, with an increased likelihood that subjects will meet the prerequisites for the trial. For example, the greater metropolitan areas of cities like São Paulo (11 million), Rio de Janeiro (5 million), Buenos Aires (13.4 million), and Mexico City (21 million) provide access to a broad range of potential study participants. Latin American countries also offer a wide ethnic diversity, due to significant immigration from Europe, Asia, and Africa.⁵

The doctor/patient relationship among Latin Americans is very strong, leading to a high level of willingness to participate, compliance, and retention throughout the course of a trial. As people learn more about the benefits of clinical trials, such as gaining access to new therapies and receiving better medical care, they are also more eager to participate. Finally, in the authors' experience, many Latin Americans are motivated by the altruistic aspect of contributing to the body of knowledge around the drug or treatment.

As with any clinical trial, it is important to understand the epidemiologic features of a region before locating a study there. For example, both Chile and Peru have a high incidence of gastric carcinoma.⁶ Gallbladder cancer is also frequently seen in Peru.⁷ The incidence of cervical cancer and other HPV-related tumors is high across Latin America. Other types of tumors, such as breast, lung, and colorectal have incidences similar to the United States and Europe.⁶

Infectious diseases like tuberculosis and HIV are still a challenge even though there are concerted efforts to reduce transmission.⁸ Finally, seasonal diseases like pneumonia and flu occur at different times of year in the southern hemisphere relative to the northern hemisphere, making Latin America a well-suited region to conduct infectious disease studies, with a seasonal component so that sponsors don't have to wait to conduct their trials.

Health care and ethical considerations

Health systems vary from country to country, but most have a distinction between public and private institutions. Either type can conduct clinical trials, although there are going to be epidemiological, social, and cultural differences in the type of population being assisted. These factors will be relevant when performing site selection in connection with a specific clinical trial.

The standard of care for different pathologies and procedures is about the same as that found in the United States or Europe; new drugs are commercially available in most Latin American countries, although they may not be affordable for all segments of the population. This makes it possible both to find patients who have been on a previous treatment and to find those that are treatment naïve.

No examination of global clinical trials would be complete without a close look at the ethical considerations involved. One area of significant concern is the fact that some Latin American populations are poor, illiterate, and without access to regular health care. This type of participant is especially vulnerable, highlighting the complications around enrollment, even with careful attention to informed consent. That's why the role of the ethical committees in reviewing and approving the proposed trials is so critical and relevant.

Ethics involving the conduct of the trial and the safety and welfare of the patients are paramount. They emphasize that sponsors and CROs must carefully select investigators and staff who are committed to protecting the patient. Investigators and staff must be able to inform patients while not coercing them. Ethical committees must audit participant sites to ensure that study subjects are adequately protected.

Sponsors and CROs, in partnership with the ethical committees and regulatory authorities, are obliged to review every study protocol from an ethical perspective particularly around the informed consent form. Informed consent is the best tool available to balance the patients' trust in their physicians with the ethical considerations of their participation in the study. Extra care is needed when patients may be poorly educated or may have no other options for treatment. All parties involved in the study have the obligation to ensure that the consent form is written and presented in a way that is understandable to the patient.

Clinical trials challenges

Despite the clear benefits of running trials in Latin America, there are also some significant challenges to consider before starting. One of the most difficult, given that most studies originate in countries outside of Latin America, is language. Not only is careful translation critical to the logistics and procedures involved, it is even more crucial to ensuring the safety and ethical treatment of study participants—particularly in the area of informed consent.

Although most of Latin America speaks Spanish (with the exception of Brazilian Portuguese), there is a tremendous amount of local variation in the meaning of some words, which makes them quite different from standard Castilian Spanish. This requires a deep review by local people in order to guarantee that both site staff and patients understand everything required during the trial.

In addition to language differences, there are regional and cultural differences that come into play. Latin Americans' relationship with their physicians tends to make them more trusting and unquestioning; they'll listen to their doctors without some of the pushback seen in other Western nations. Patients may participate more willingly in trials because of their doctor's recommendation, but there needs to be a careful balance between the actual benefit to the patient and their desire to please their doctors.

Best practices for better outcomes

On planning. Don't underestimate the time it will take to go through the regulatory and import process. Particularly in Brazil, it takes longer to start than in other countries. However, changes put in place in December 2009 have reduced the review timeline process by about six to eight weeks.¹⁷

On process. Due to the nature of the regulatory process in Latin American countries and the cycle time to trial approval it is vital to submit documentation correctly the first time. Take the time to thoroughly review all documents two or three times to avoid mistakes. It may also help to have a checklist for sponsors so they understand the detailed documents that must be provided for the local and national regulatory packages. Documentation checklists are highly variable dependent on the country in which the trial is being conducted, the type of trial, and many other factors.

On communication. Take time to understand how all parties like to work and what they prefer as a communication channel. The use of email should be carefully considered with respect to language and culture differences. Email is a powerful tool, but can also lead to misunderstandings, so it is important to pick up the phone often to ensure clarity on important issues. Invite sponsors to visit potential sites, since it may be difficult for someone who hasn't been in the region to understand the capabilities of the area. Seeing the facility and talking to the investigators and staff are great ways to learn more about how things are conducted.

On culture. It is particularly important to have someone local involved with the trial who understands and can address regional issues and how cultural differences could affect participation. For example, patients must clearly understand that they may not receive a direct benefit by participating in the study. Patients' willingness to participate is connected to their understanding of the process, education, and values, which might vary regionally.

On respect. To be successful in Latin America one must have an authentic respect for culture, custom, and language when conducting global trials. Local resources will likely have a greater understanding of this than study sponsors. For example, the local managers understand specifically what the ethical boards are looking for in the informed consent and have developed templates. Sponsors that have insisted their own wording be included in the informed consent form have often had those forms rejected.

Conclusion

Global clinical trials are best served by recognizing, valuing, and respecting the diversity of every region involved. It pays to learn more about what Latin American countries have to offer, and which of them best fits the needs of a specific study. There are many experienced clinical research professionals in Latin America who can guide study sponsors in areas such as population demographics, regulatory timelines, and regional capabilities. It pays to listen to these regional experts for the best possible outcome of a Latin American clinical trial.

Ofelia Rodriguez Nievas,* MD, is the Managing Director, Latin America, email: ornievas@clinipace.com, and Sandra Grosworsel Schefler, RPh, MBA, is the Managing Director, Brazil, at Clinipace Worldwide.

*To whom all correspondence should be addressed.

References

1. R. Chin and L. Safar, "Clinical Trials Go Global: Next Stop, Latin America," Pharma, July/August 2009, 16-19.

2. http://www.clinicaltrials.gov.

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7. M. Lazcano-Ponce, N. Munoz et al., Epidemiology and Molecular Pathology of Gallbladder Cancer, CA: A Cancer Journal for Clinicians, 51 (6) 349-369 (2001).

8. World Health Organization, http://apps.who.int/globalatlas/dataQuery/default.asp.

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10. http://www.anmat.gov.ar.

11. http://www.anmat.gov.ar/Legislacion/Medicamentos/Disp_5330-97_actualizada_2008.pdf.

12. http://www.ispch.cl/.

13. http://www.ispch.cl/ensayos-clinicos.

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16. http://portal.anvisa.gov.br/.

17. Clinpage http://www.clinpage.com/article/brazils_regs/C15.