Latin America: Ripe for Clinical Research?


Author: F. Bruce of Scrip

In recent years, clinical research activity has seen a huge shift towards the emerging markets of Asia-Pacific, Central and Eastern Europe and Latin America. In 2007, 42% of patients taking part in clinical trials worldwide were from emerging economies, more than double the figure in 2002, approximately 10% of these patients were from Latin America. “Five years ago sponsors came to Latin America mainly for rescue studies [when sponsors include an emerging region to meet enrolment targets on time]. Now the region is involved in planning from the very beginning.” Approximately 1,500 trial sites are set up in Latin America each year, based on the number of US FDA 1572s filed (forms filed by investigators if the product undergoing trial is to be marketed in the US. “No one wants to go without Mexico, Chile Colombia, Brazil or Argentina because they have the strong researchers, key opinion leaders and they are bigger markets,” he says. These three countries are the most developed clinical trial markets in the region, in terms of the number of active, completed or recruiting studies listed on the US National Institutes of Health’s Clinicaltrials.gov database (see Table 1). Mexico, Brazil and Argentina have been active on the global clinical research map for 15 years.

Table 1: Clinicaltrials.gov-listed studies in Latin America
Brazil 1039
Mexico 845
Argentina 738
Chile 377
Peru 366
Colombia 239
Cost Rica 92
Guatemala 88
Panama 65
*Source: Clinicaltrials.gov, October 2008

FDA audit results and they conduct a large number of trials each year – so they clearly can be considered the region’s “emerged” markets. Meanwhile, the region’s up and coming markets – in effect, its very own “emerging” economies – include Chile, Colombia and Peru. “They are attracting more and more FDA inspections and the results are good. They are therefore gaining recognition,”

Emerging Regions’ Pros

As in other emerging regions, the quality of data generated throughout Latin America is good and it competes well with developed markets such as the US. Since 2006, 5.4% of US-based clinical trials inspected by the country’s FDA have received notifications of official action indicated. “This means that around one in every 20 sites inspected in the US is considered by the FDA inspector as having serious problems,”.

For trials conducted outside the US, this figure was just one in 187. Moreover, of the 90 inspections carried out outside the US in 2007, 12 were conducted in Latin America and all received positive results. This disparity perhaps arises because most sponsors venturing into “non-traditional” regions put a lot of emphasis on monitoring and education. Investigators in emerging regions are also eager to learn and to be compliant. “They don’t take it for granted that they have an opportunity to take part in a clinical trial,” says diverse Latin American CROs notes that, like the Asia-Pacific region and Central and Eastern Europe, Latin America promises a large number of treatment naive patients as well as higher enrolment rates (see Table 2). Patient retention is also very good in Latin America, which is vital for the sustainability of trials. This is largely down to good patient/investigator relations, they indicated.

Table 2: Variation in global patient recruitment rates:
Region Average number of patients enrolled per site
South and Central America 4.6
Asia-Pacific 5.78
Central and Eastern Europe 6.27
Western Europe 3.08
US 1.92
*Source: Lehman Brothers November 2007

The Cost Advantage

Emerging regions, Latin America included, offer a cost advantage compared with traditional markets, a key consideration given the rising costs of pharmaceutical R&D. Developing a new drug all the way to market now takes 10-15 years and more than $1.2 billion of investment, according to the Tufts Center for the Study of Drug Development. Conducting a trial in Latin America costs about 70-80% of an equivalent study in the US or Western Europe, where experience and expertise make clinical research more expensive. Added to this, “Latin America’s pharmaceutical market is growing well, meaning that there is strong sales potential for the product after it is approved”.

Retail pharmacy sales in Argentina grew by 20%, considerably outstripping growth in Europe (+3%) and the US (+1%). Argentina, Brazil and Mexico together generate around 80% of Latin America’s sales. Retail pharmacy sales in these three countries totaled $24 billion in the 12 months to July 2008 (see Table 3).

Table 3: Latin American retail pharmacy sales, 12 months to July 2008
Country Retail sales ($ billion) % growth
Brazil 12.2 +10
Mexico 8.8 +5
Argentina 3.0 +20
Total 24 +9
*Source: IMS Health

Latin America also offers another unique advantage: the common language of Spanish (except, of course, in Brazil where Portuguese is spoken). This factor can save time, money and HR requirements. “A CRA [clinical research associate] coming from Mexico, Chile, Argentina can work in Uruguay or Colombia and use the same language, but in Western Europe a CRA going from France to Spain would need to speak two languages”. The common language also reduces translation costs.

The region is also particularly attractive to North American-based sponsors because of its proximity. This means that sites can be easily visited; this is particularly important with proof-of-concept trials in which companies need to access patients and data and to talk to investigators.

Regulatory Progress

Latin America’s clinical research “growth spurt” is a relatively new phenomenon, and one that has thrown up a number of challenges for its regulators. Much of the region’s legislation was drawn up in the 1990s and a number of resolutions have since been drafted on a country-by-country basis. “It soon became obvious that some countries had so many layers and disconnecting processes in ethics and regulatory review processes. Reducing regulatory and start-up timelines has therefore become a priority,” says Dr Gustavo Kesselring, president of the Brazilian Society of Pharmaceutical Medicine.

Start-up can be very lengthy (see Table 4) and the process generally involves three phases: regulatory review, contracts being signed by sponsors and investigators, and the logistics of getting everything into the country. Brazil provides an interesting case study on this point. Despite the country’s size and potential to enroll large numbers of patients, Brazil has not received its fair share of trials, he adds. This is largely because it is still the slowest country in the region in start-up terms, despite shaving six weeks off the process through recent regulatory changes (see Box 1). “No one wants to wait that long to get started, unless the trial has a long enrolment time,”.

Table 4: Total start-up times in Latin America
Country Start-up time (months)
Mexico 3 - 4
Colombia 4
Chile 3 - 4
Peru 5
Argentina 5 - 6
Brazil 9
Source: ESTERN Medical Latin American operations

However, as Latin America’s various regulators begin to address this issue (see Box 1), another bottleneck is already emerging – the issue of getting sponsor/site contracts signed. Often, contracts must be drafted in Spanish (or Portuguese in Brazil) to be valid. Therefore, they must be translated back and forth between that language and English, for the benefit of sites and the sponsors’ lawyers respectively. This is a slow process. “One word can change a lot depending on the translator you use, and the document can be quite different by the end of the process,” he says. Nevertheless, the Latin American region is undoubtedly moving forward. One major step was the creation of the ‘Document of the Americas’, which sets out the criteria for harmonized GCP in the region.

Box 1: Recent regulatory changes in Latin America

Mexico: Customs authorities have removed the requirement for import licenses for drugs or for export licenses on blood serum samples. This has reduced the start-up timeline from 3.5-4.5 months to 3-4 months, bringing Mexico’s figures in line with EU countries.

Chile: Regulations on GCP compliance in line with the Document of the Americas are being drafted.

Colombia: A resolution-making adherence to GCP compulsory was published in June 2008. All bodies involved in clinical trials were given six months to define a plan for development and implementation and compliance with GCP. They have two years to obtain GCP certification.

Peru: Regulations were updated in 2007 to achieve full compliance with ICH guidelines. Start-up times have been reduced by 1.5 months.

Argentina: In November 2007 Argentina published a resolution, which brought GCP guidelines in line with the Document of the Americas.

Brazil: National Ethics Committee review and Competent Authority reviews for approval now take place in parallel. This change could potentially reduce approval times from 10 months to 8.5 months.

It took representatives from Argentina, Brazil, Chile, Costa Rica, Mexico, the US and Venezuela 10 years to draft before the document could be approved by the Pan American Health Organization in 2005. It now serves as a guideline for investigators and agencies and is gradually being implemented on a country-by country basis. Argentina and Colombia were among the first to incorporate it. As in other emerging regions, concerns have also been raised over the ethical conduct of clinical trials. Critics claim investigators may recruit uninformed patients, who may be too easily enticed because of otherwise limited treatment options. However, such concerns are exaggerated, says Dr Kesselring. Investigators all over the world are under pressure from pharma companies and CROs to recruit and the sites that recruit the most patients earn the most money, he says. “If uninformed patients are included in a clinical trial, it is down to problems with the site’s informed consent process or GCP training at a local level.

This can happen in Brazil, Mexico, the US, Germany or Botswana,” he says. Furthermore, regulators are taking measures to safeguard patients. Brazil, for example, recently issued new guidelines on access to after-care and the use of placebo in clinical trials.

Both elements comply with the declaration of Helsinki, the most widely accepted ethical guidance for biomedical clinical research, says Dr Kesselring. Meanwhile, the Buenos Aires Declaration on Ethics and Clinical trials was recently approved by the First Latin American Workshop on Ethics and Clinical Trials (which took place in that city in May 2008). The groups behind the initiative hope it will become a reference for guidance on ethics in the region.

However, it is yet to be accepted by the global pharma industry and national regulatory agencies. One additional challenge for Latin America will be to increase its pool of highly trained staff, including investigators.

Encouragingly, some progress has already been made on this front. Associations including the Brazilian Society of Pharmaceutical Medicine and the Argentinean Society of Pharmaceutical Medicine are addressing these training needs, says Dr Kesselring. CROs and pharma companies are also running training programmes, as are universities such as the Federal University of Sao Paulo (UNIFESP) and the Sao Paulo Santa Casa Medicine College. Sponsors will keep coming to emerging regions, particularly as pharmaceutical companies aim to increase the number of trials they conduct outside of the US and Europe from 20-30% to 40-50% over the next few years. “They will definitely come to Latin America.”