The outsourcing of clinical trials to Latin America, given the ever-growing cost associated with Europe and North America, is becoming increasingly attractive to pharmaceutical companies looking to reduce costs. Latin America is a region of particular interest for clinical trial outsourcing, with trials having been conducted in the region for several decades now. But what are the wider implications of this move, and will the movement continue to grow? And how has this influenced the demand for medical translation services for the region?
According to The New York Times, 78% of the people who participated in clinical trials in 2008 were enrolled outside of the United States, and a significant majority of these were in Latin America. Latin America has been very popular among sponsors conducting trials outside the United States for a few reasons: populations within dense regions allow for quick recruitment and higher numbers of patients per location, the expenses are lower and there is an ethnically diverse population similar to that found in the United States or Europe.
The medical training in the region is comparatively high; doctors are aware of good clinical practices and other industry guidelines, and aim to adhere to these wherever possible. Another important factor is that medical centers, doctors and hospitals are eager to participate in the studies, as they bring money and jobs to the region as well as contact with status-enhancing international research.
Successful clinical trials rely on a variety of factors, and Latin America — in particular Brazil, Mexico and Argentina — meets many of these criteria:
Willing target population. Latin America has densely populated areas, with an increased likelihood that many people will meet prerequisites for a clinical trial.
Investigational teams. Many investigators place a high value on the scientific and academic aspects of the trial, and are pleased when they are invited to participate.
Health systems. Latin American countries have become desirable sites for studies, both because they have adopted regulations that mirror those recommended by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and because the regulatory authorities are committed to keeping them updated.
Standard of care. It is possible to both find patients who have been on a prerequisite treatment and to find those who are “treatment-naïve.”
Epidemiological considerations. Seasonal diseases like pneumonia and flu occur at different times of year in the southern hemisphere, making Latin America a well-suited region to conduct infectious disease studies with a seasonal component. This way, manufacturers do not have to wait an additional six months to conduct their trials.
As a result of these factors, Latin America has seen the highest growth rates in clinical trials among all the emerging markets.
Potential problems with Latin America
Superficially, Latin America appears to be a true clinical trial paradise; however, it is only once the trial is in motion that the potential problems can begin and the learning experience for the sponsor really starts.
One of the most frequent problems for delays is due to the differing regulatory requirements surrounding informed consent forms (ICFs). This can be avoided by proper preparation and research. Many sponsors do not take into account the lower education and illiteracy levels found in the region, and will find that straight translation of approved ICFs in Europe may not be approved in Latin America due to their complex wording.
Religious issues may also cause a problem; for example, the request for the sexual history of a woman in many regions in Latin America may be grounds for rejection by the site. The evangelical church, very popular in Latin America, is another example of a potential conflict as it prohibits blood transfusions of any kind.
In addition, “benefit assessments” by Latin American ethics committees focus on benefits for the patients and carefully analyzes factors such as the health care context and social setting of the subjects. The use of placebo, payment for participation, consent process and the expectation of post-study treatment may be required to achieve ethics approval. This is a different process than that found in Europe or the United States.
Translating materials and established protocols into Spanish or Portuguese is often viewed as the only direct communication cost associated with working in the region. The unseen costs, such as localization to the particular region’s laws and culture, can be overlooked and thus lead to later unforeseen costs or negative implications for the trial.
Estimates show that in the United States, 66% of subjects enlist in clinical trials independently of their doctor’s advice. In Latin America, however, 80% of subjects are offered enrollment into studies via their doctors. This is a critical aspect to bear in mind when designing patient materials. Doctors are often very protective of their patients, as they are often less able to make fully informed medical decisions; this predisposes doctors to be more paternalistic.
The other potential problems include long trial start-up times, excess bureaucracy and unclear regulation in an environment of competitive enrollment, all of which result in some clinical trials failing to get off the ground in the region.
For things to improve, sponsors need to work closely with local regulators, who in turn need to be more in touch with local practices in order to better understand requirements. By understanding the local environment, sponsors will be able to plan for the high recruitment rates that currently offset the long delays for study start-up. Regulators need to define clear processes, procedures and timelines, and commit to sticking to them. A look to the Asian competitor regions for clinical trials shows that they are moving faster and more efficiently in this regulatory field.
An array of legal problems can present themselves when conducting clinical trials in Latin America. A mutual understanding of the legal environment will help streamline clinical trial agreements and avoid contracts that are legally unenforceable.
In contrast to several emerging regions where there are multiple language requirements, Brazil has a single translation requirement for regulatory documents. A unified Brazilian Portuguese is spoken throughout the country, unlike the numerous dialects and variations of Spanish. For the rest of Latin America, Spanish is by far the most widely-spoken language. With documents being localized to each specific country, ICFs may also require localization to the native dialect of indigenous people such as Amerindian languages, if they are participating in the study.
One final advantage for Latin America is that the focus on just only two languages, Spanish and Portuguese, albeit with their local variations, provides an excellent advantage over comparable regions such as Europe. However, Spanish-speaking countries within Latin America have subtle linguistic differences that can result in miscommunication and clinical trial breakdown if not resolved.
In 2008, The Buenos Aires Declaration on Ethics and Clinical Trials was unanimously signed by participants in the First Latin American Workshop on Ethics and Clinical Trials workshop. This declaration was issued in response to the rapidly increasing number of clinical trials in the region and ethical issues related to clinical trial approval in Latin America.
In relation to specific concerns regarding ethical violations, the declaration specifically addressed the need for cultural considerations and competent translation:
1) In Latin America, protocols originating from outside the region must be translated by competent expert translators for presentation to local authorities (the regulatory agencies, ethics committees and so on) into the language of the country where the clinical trial takes place (Spanish, Portuguese or French).
2) The informed consent should fulfill the following requirements: firstly, informed consent forms originating from outside the region must be translated by competent expert translators; secondly, persons totally independent of the clinical trial must verify that all social and ethnic strata that participate in the trial understand clearly the content of the informed consent form; and thirdly, when indigenous populations participate in the trial, the informed consent form should be presented to them in their native language.
Translation buyers in the clinical arena, including Latin America, are used to dealing with academics, doctors and pharmaceutical managers. There is a certain tone and expectation level that is required to be reciprocated when engaging these buyers.
An understanding of the science, processes and requirements of a clinical trial is more likely to be appreciated than, for example, computer-aided translation tool knowledge. This would apply not only to direct clients but also to medical translation agencies that work within this atmosphere. Creating a sense of academia, reliability and an understanding of the wider clinical trial issues will be invaluable when translating for the sector.
It is not only the tone of formal communications that it is essential to understand and get right, but also the tone and appropriateness of the materials in production. An understanding of the end use of the materials is useful but even more so is an understanding of the target audience.
Adjusting the tone of a translation for a congress presentation, a patient information leaflet or a pediatric clinical evaluation can be difficult and requires research on both a clinical and cultural level.
The result is that the materials a specific translator can work with are limited to his/her native country, in particular if the target audience is children or patients. The less academic the target, the more country-to-country variations will appear. For example, a clinical protocol might vary a little across Latin America, but a series of pediatric psychological evaluation questions would vary significantly across countries even within the same language, with each target country requiring not only review by a native speaker but also a clinician with relevant qualifications.
Regulatory landscape in Brazil
The clinical research sector first started to evolve in 1996, when the country established regulations in accordance with international standards, specifically the IGH Guidelines for Good Clinical Practices (GCP).
The majority of clinical trials conducted are Phase III trials according to the governing body Agência Nacional de Vigilância Sanitária (ANVISA). 80% of these clinical trials are conducted by multinational companies. Phase III studies are focussed on a large range of patients, with the objective of determining the risks and benefits of the target medicine.
In Brazil, the National Health Council (NHC) approved a resolution that “research involving human subjects must ensure the research subjects the benefits resulting from the research project, in terms of social return, access to procedures, products or research agents” (NHC 1996, III.3(p)). The resolution also provides that “in case of research conducted abroad or with external cooperation” evidence “of commitments and advantages to the research subjects and to Brazil, which will result from the implementation of the research” must be submitted (NHC 1996). Another resolution states that “access to the medicine being tested must be assured by the sponsor or by the institution, researcher, or promoter in the event its superiority to the conventional treatment is proven” (NHC 1997, IV.1(m)).
In Brazil, only out-of-pocket expenses are reimbursed. Patients receive trial-related medical care at no cost, but no other financial incentive is permitted. This information is stated in numerous places in Resolution 196/96 by ANVISA.
As a result of the continued interest in Brazil, a proposal was announced to consider for the first time that patients and volunteers be remunerated for their participation. This is common practice in the UK and the US but is prohibited in Brazil. However, this new proposal was eventually rejected, with one possible reason being that it “could lead to exploitation; it’s one thing to pay for transport, but another to receive 10,000 reals for one injection.”
The debates regarding payments highlight some of the challenges of working in a less developed region, where laws and regulations that may function in the United States and United Kingdom become much more challenging in a different cultural and socioeconomic environment.
Brazil conducts the highest volume of studies in Latin America and the second highest out of the BRIC nations. Despite the six-month regulatory waiting period in Brazil, compared to just two months in other countries, Brazil still maintains its success as it has an ability to recruit patients very quickly. This shows Brazil’s clinical trial potential, and despite current legal and bureaucratic delays, which are slowly being improved, it is currently an attractive location and set to improve as regulatory and legal factors improve, helped by strong national interest in improving the law as well as organizations such as the Brazilian Association of Clinical Trial Organizations, leading the way for governments and multinational organizations to work together.
Of the 9,500 qualified doctors in Brazil, just 10-20% are in contact with the clinical trial system. The result is that there is a lack of experience being generated in-country by Brazil, meaning that innovation and scientific progress are extremely dependent on the qualitative improvements of medical teaching in Brazil. For post-graduate studies with a focus on clinical trials, there is a need for a much higher number of doctorate professors, which can only be achieved through the completion of unique scientific research. The reality is that it is much more common for further specialization to occur for personal professional gain, as this is where the immediate demand is, rather than the completion of unique clinical research.
It seems that the Latin American region has the ingredients for an optimum clinical trial environment, and the sector is gaining momentum from recent investments and development.However, there are cultural, regulatory and educational issues that need to be addressed by the sponsor and at the local level in order for the recent continued growth to be sustained. The region will continue to be of great interest to multinational clinical research organizations and pharmaceuticals for its large, diverse and rapidly expanding population (much of which is treatment-naïve), shortened approval times, improved GCP compliance and an emergence of diseases predominant in developed countries. Successful patient enrollment and retention rates, and proximity to Western biopharmaceutical companies, are additional factors.
There are significant hurdles that foreign sponsors must also consider, however, including linguistic and cultural barriers, as well as other socioeconomic factors such as poverty, illiteracy and — perhaps even more dangerous — misinformation. Successful outsourcing of clinical trials to Brazil therefore involves an understanding of these factors, and how they affect clinical research. It will also depend on the local development of the country’s infrastructure and regulatory support for trials, and how the region develops relative to its competitors over the coming decade.
Global impact on
As the above advantages of conducting a clinical trial in Latin America increase in importance, so will the number of trials in the region. Over time, governments and regulatory bodies have begun to develop significantly in the region and will continue to do so alongside the trial development.
The result for the translation industry is the responsibility to accurately and faithfully translate both the increasing number of legally required and logistically necessary materials, while evaluating both the scientific content as well as adjusting the tone to the relevant audience. It is the responsibility of the end client, agency and translator to ensure that all of these laws, subtle nuances and quality communications are rendered for the continent in order to facilitate the trial development.