Karen Politis Virk

Many emerging countries, such as India, China, Mexico, Brazil, and Russia, are rapidly becoming prominent outsourcing locations for clinical research. A wider availability of patients, low operational costs, and positive patient attitudes toward clinical trials has driven the trend. These developments have been acknowledged by the major regulatory agencies; data generated in these regions now represents a growing portion of regulatory submissions. For example, the FDA's Office of International Programs has extended its focus on emerging markets, with formal offices set up in China and India to monitor and oversee developments.

 As the number of clinical trials outsourced to emerging regions continues to rise, 65% of FDA-regulated clinical trials conducted by major pharmaceutical companies are expected to be outsourced to emerging countries by 2012,

  sponsors have to address several new challenges.  

Adequately meeting specific regulatory requirements in each country and addressing the vast linguistic and cultural differences among various patient populations are among the biggest challenges sponsors must face. Language and culture are also important factors in dealing with local regulatory authorities. Regulatory documents commonly must be translated into the country's official language, and approval must often be translated back for other regulatory authorities. Any differences in regulatory processes and specific translation requirements must be addressed. 

Most clinical sites are located in major cities, and as a result of urbanization trends, patient populations often include several ethnic minorities who speak languages other than the country's official language. Although this results in greater genetic diversity, it further complicates the issue of linguistic and cultural barriers. To ensure success, therefore, the translation of clinical trial documents must be performed by experts who are native speakers of the required language, are familiar with the culture, and have a background in clinical research. In addition, partnering with a local CRO or language service provider with experience in that country will better ensure regulatory approval.  

The translation of clinical trial documents involves more than just simple translation from a source language into a target language. In addition to translating documents for regulatory authorities, patient-related materials and informed consent forms must be carefully translated into the patient's native language, and the text must be culturally adapted for the target subject population. Following initial translation, the text undergoes a review process performed by a separate group of expert translators. The review is then back translated to ensure that the original meaning has not been "lost in translation." To contain costs and increase translation efficiency, professional translators create or refer to existing translation memory (TM) or glossaries. These contain an archive of preferred clinical trial terminology and accepted medical terms that are commonly used by the majority of professional translators in a particular language. However, there are languages in which these terms are less defined. For example, researchers in one South African study found that language created barriers to informed consent due to a lack of established local words for terms such as "randomization" or "placebo."

  In fact, one of the most common problems in international trials is related to inaccuracies in the translation of informed consent forms. 

In addition to creating barriers to informed consent, linguistic and cultural differences can affect patient reporting of disease symptoms and adverse events, and interfere with the diagnosis or treatment of patients participating in clinical trials. Several clinical studies have demonstrated that a patient's language and culture influences their perception of disease and symptoms. These factors must therefore be taken into account in the interpretation of patient data and in the translation of all patient-related materials.  

Clinical studies commonly require patients to fill out various types of study questionnaires such as quality of life questionnaires or health assessment questionnaires. It is essential, however, that these questionnaires are linguistically validated and culturally adapted to ensure accuracy of patient information. Inaccuracies can result in changing the outcome of a study, or even cause a study to be invalidated. Rating scales associated with these questionnaires may make this process substantially more difficult, as even everyday items or phrases may have significant differences. One study, aimed at culturally adapting HAQs involving rheumatoid arthritis patients at Ankara University in Turkey, reported that several linguistic changes needed to be made to the translated questionnaires to account for cultural differences, (e.g., "shampoo your hair" needed to be modified to "wash your hair," because both shampoo and soap were used in Turkey for washing hair at that time).

Another study focused on diagnosing clinical depression in geriatric patients in Malaysia reported that one of the questions in the study questionnaire had absolutely no discriminatory value in differentiating cases of depression among Malay patients: "Do you prefer to stay at home, rather than going out and doing new things?" Since in Malaysia the main emphasis is on family living rather than individual lifestyle, patients had a higher tendency to give positive response to this item, despite their depression.

  As a result, study questionnaires must often undergo a series of reviews to address linguistic and cultural barriers. Ultimately this means greater time and expense, as translation experts must work with patients and physicians in order to ensure that the information in the translated versions is as accurate and effective as in the original. 

To make the issue more complex, some countries have multiple translation requirements. In India, for example, Hindi (spoken by 30% of the population) and English (fluency in 5% of the population) are two of many official languages. In addition to over a dozen official languages recognized by the Indian government (some statistics quote 22), there are many more regional languages recognized at the state level. Furthermore, depending on the patient population, there are hundreds of dominant languages and dialects that must be considered. As a result, informed consent forms and other patient materials frequently need to be translated into a minimum of eight to 10 regional languages. In Singapore, Malay, Mandarin Chinese, Tamil, and English are all official languages. In addition to these languages, there are a significant number of speakers of Hokkien, Cantonese, and other minority languages. Thus, identifying the patient population and the respective translation requirements requires an adequate knowledge of the country and its people.  

In contrast, in Russia the majority of the population speaks Russian, the only official language. Although for the most part this simplifies the translation process, there are many Russian ethnic minorities and indigenous populations for whom Russian is a second language. As a result, teaching is presently conducted in 75 different national languages throughout Russia.

 Furthermore, there are several regional dialects, divided according to their location to Moscow. Although, in major urban centers where clinical sites are located, these differences are less of an issue; sponsors must consider the particular patient population. Brazil is another country that has a single language translation requirement: Brazilian Portuguese. Although the country's official language is spoken with only slight regional variation, other minority and indigenous languages may be dominant among certain ethnic groups, including several Amerindian languages. For example, Tupí is one of the most dominant indigenous languages along the coast of Brazil, and Guaraní is spoken by close to four million people in Paraguay and Brazil.

  Spanish is a dominant minority language, especially near the borders, composed of approximately one million speakers. In addition, there are several other minority languages such as Korean, Italian, and Japanese spoken by large immigrant populations. 

Thus, even in countries where there is only one official written language, patient populations may be composed of different ethnic minority groups who speak dialects or languages other than the official national language. This is well demonstrated in China, where, although Mandarin Chinese is both the only official and written language; there are several other dominant languages spoken throughout the country, such as Shanghainese (90 million speakers), Min (50 million speakers), Xiang (25 million speakers), and Cantonese (70 million speakers). In addition to these, there are numerous other minority and indigenous languages. Moreover, there are two different character types of written Mandarin, and depending on the patient population, translators must know which one to use. In mainland China, the original or traditional Mandarin characters have been changed to simplified Mandarin characters, a more simplified writing system. However, Chinese speakers in Taiwan and Hong Kong still use traditional characters. This is further complicated by pre-existing linguistic differences between respective users of simplified and traditional characters. 

In most Latin American countries, despite the common official language, Spanish, there are many spoken variations. For example, Mexican Spanish differs significantly from Argentine Spanish, and both in turn differ from Castilian Spanish. In addition, there are regional variations among Spanish speakers even within the same country. A look at differences among regional dialects spoken throughout Mexico alone demonstrates the complexity of this issue. Currently, there are more than 50 native Mexican languages considered to be Mexican Spanish dialects.

 Moreover, some patient populations may have limited Spanish proficiency, thus other indigenous and minority languages must also be considered. 

In many African countries the issue of language is especially complicated. In South Africa, for example, there are 11 official languages including English and Afrikaans. Among these, Zulu is the most dominant with approximately 10,000,000 speakers. In addition to 11 official languages, there are several other dominant dialects and languages depending on the particular region and ethnic group. Senegal, although not as established in clinical research as South Africa, currently conducts a significant amount of research in collaboration with Western institutions. In Senegal, although French is the only official language, there are several other—14 in total—national languages. Among these, Wolof has the greatest number of speakers and is native to a third of the population. In addition, there are other minority languages such as Portuguese Creole and Cape Verdean Creole that must be considered. 

Identifying the target patient population and translation requirements is only the first step in addressing language barriers. Ensuring quality and accurate translation is just as crucial. Inconsistent or poor translations have been known to cause serious problems, including delays in regulatory approval and interference with obtaining informed consent and patient data. These issues, however, can be overcome to a large extent with proper clinical trial management. According to current international guidelines, sponsors must employ professional translators, particularly when translating patient information and informed consent. By partnering with language service providers that have experience in a specific country or region, sponsors can ensure that any linguistic barriers are properly addressed (see Table 1).  

Although each country's culture should be considered separately, there are several common factors among countries in emerging regions. For example, in most emerging countries patients traditionally hold their physicians in high regard. Despite the fact that this strong relationship greatly facilitates patient recruitment in these countries; it must also be considered for other effects on clinical research. For example, as a result of this trust, patients tend to accept their physician's recommendation to enroll in a clinical trial without questioning or fully discussing other potentially beneficial treatments. Although foreign sponsors must make an effort to clearly communicate their expectations to ensure that ethical standards are maintained, they must also respect the cultural differences and the different approach to practicing medicine in other countries. 

Another example of this is the censoring of medical information by physicians. It is common in many emerging countries for physicians to withhold "bad news" from their patients because it is considered to negatively affect the outcome of a patient's treatment. As a result, terminally ill patients are not told of their disease status, and patients may not know all of the risks associated with clinical trial participation. In many countries this information is disclosed only to family members who are also more likely to be responsible for deciding the patient's medical treatment. While such practices are widely accepted, they do not comply with the informed consent procedures set by countries that are more established in clinical research.  

In addition, cultural factors often have been shown to have an impact on patients' perception and the reporting of symptoms or adverse effects. For example, several studies have indicated that there are significant differences in the perception of pain due to cultural attitudes. Cancer studies involving Asian American patients indicate that Asians tend to underreport pain due to their belief that they must accept it as part of their illness.

  Similarly, some studies have indicated that Russian patients tend to underreport pain due to the belief that it is a show of strength.

Cultural factors may also influence who receives healthcare in some societies. In Brazil, for example, societal norms dictate whether a woman participates in a clinical trial—the decision is often made by male family members such as a father or a husband. In a conservative Islamic society such as Senegal where homosexuality is taboo, it is often difficult for men infected with HIV, or consequently TB, to obtain healthcare without facing discrimination.

Some cultural beliefs may directly interfere with ethical standards and pose a serious dilemma for foreign sponsors. For example, unlike most Western cultures, in the Middle East many patients may consider the signing of an informed consent form unnecessary as verbal agreements are already binding.

Understanding cultural factors will also prevent sponsors from overlooking other aspects of local life that will impact subject recruitment. For example, in India, agricultural workers form a large section of society, but since their income is low and employment irregular, they must maximize all opportunities to support themselves and their families. Official figures suggest that over 70 million people are agricultural workers, primarily in small towns and villages.

 For such individuals, harvesting season is an important period, as they work jointly with their families to earn income that may need to last the whole year. As a result, during harvesting season, patient inflow to hospitals tends to be less, thereby leading to slower subject recruitment, and disruption of follow-up visits if the events fall during those days. However, experienced investigators can make use of staff, translators, study nurses, and other personnel who can understand subjects' cultural differences to devise alternative arrangements that take into account such factors. 

In many emerging markets, free or subsidized medical treatment is not available, participating in a clinical trial may be seen by these subjects as a means to ease some of their additional economic burdens to access healthcare. While it is important to acknowledge such socioeconomic factors, care must be taken not to assume that those who are poor and illiterate lack common sense or intelligence. Furthermore, ethically, every effort must be made to provide them with information that they can understand so that they can participate in trials of their own free will. It must be remembered that these potential subjects have an equally strong commitment to their life and families as those who are richer and more educated. If they are not convinced, then as with other potential subjects, they will not participate in the trial. 

A growing percent of the population in many emerging countries currently lives near or in a major city as a result of urbanization. Rapid urbanization transforms the environment as people compete for limited natural resources and space, leading to overcrowding and poor hygiene. Consequently, this impacts both lifestyle and disease trends in these countries. The incidence of chronic diseases, such as cardiovascular diseases, malignant tumors, and mental disorders in urban areas is higher than that in rural areas and is on the rise. 

For example, according to the World Health Organization, 80 percent of people with diabetes now live in low- and middle-income countries.

  India and China currently have among the largest and fastest growing numbers of diabetes patients. Factors such as unhealthy diet, a sedentary lifestyle, smoking, and alcohol abuse have contributed to this disease trend in emerging regions. 

In addition, many patients in emerging countries may have limited access to adequate healthcare. As a result, diseases associated with poverty persist. Moreover, the incidence of infectious diseases such as HIV, TB, and malaria continue to be a serious problem in emerging countries where large numbers of infected patients cannot afford treatment. A look at statistics in many African countries, as well as countries such as India and Brazil, reflects the immensity of the problem, and dwarfs the impact in North America and Western Europe. 

More recently, several emerging countries have initiated government programs to make treatment more affordable. In Brazil, where only about 20 percent of the population has health insurance, the government has increased reimbursement and free drug coverage for patients in the public healthcare sector.

  Moreover, due to the high cost of pharmaceuticals, many emerging countries strongly support the use of generics. Balancing the cost of developing and testing new drugs with making new treatments available to more patients that have lower economic status is a serious challenge for foreign sponsors; however, it is one that must be reconciled. 

Socioeconomic factors and informed consent

Regulatory delays in clinical trials are most commonly due to problems with informed consent. In large part, this is because many sponsors are not fully aware of the significant barriers that exist among many clinical trial subjects in emerging regions. International standards for informed consent require that forms be provided at a 4th to 8th grade comprehension level. 

However, in the case of illiterate patients, there are often country-specific requirements. For example, in Mexico illiterate subjects are commonly asked to sign a second consent form that requires the signatures of two witnesses.

  Since 2008, new standards were set for trials conducted in Latin America: foreign sponsors must use competent professional translators to translate informed consent and persons independent of the clinical trial must verify that enrolled patients understand clearly the content of the informed consent form.

  In India, illiterate subjects must be accompanied by a literate relative who serves as a witness during the informed consent process.

  Furthermore, because it is such a multilingual country, sponsors must provide patients with a verbal explanation in their own language prior to signing a written informed consent form. 

In addition, new multimedia tools are available in countries where there are large populations of illiterate patients to help overcome barriers associated with limited education. For example, the "speaking book," a sound recording with pictures that explains to the potential participant their rights and role in the clinical trial, is currently in the process of being implemented in several African countries such as South Africa.

The issue of limited medical access further complicates the informed consent process. Many patient populations that live in conditions of poverty may have little or no access to any medical treatment. Thus, participating in clinical trials is the only opportunity for treatment. Furthermore, clinical research often provides patients access to new, modern treatments that would otherwise not be available to them. A look at the national statistics of the percent of people living at or below the poverty line in many emerging countries—India (between 25% and 33%), Philippines (up to 30%), Mexico (almost 50%), or Brazil (around 25%)—reflects the immensity of the challenge of ensuring the rights of patients with limited healthcare access and resources.

Clinical research criteria dictate that patients must be adequately nourished to enroll in a trial. This eliminates those living in extreme poverty. However, since most clinical trials are conducted in urban areas where there are large areas of poverty, sponsors must consider that significant numbers of enrolled subjects are living at or near the poverty line. Furthermore, sponsors must also keep in mind that despite the fact that most international sites have adopted International Conference on Harmonisation, Good Clinical Practice standards, regulatory and ethical environments are continually evolving. Finally, significant differences in regulatory processes among emerging regions remain, and standards set by countries more established in clinical research may not apply everywhere. 

In the near future, it is expected that emerging countries will conduct a greater number of clinical trials than previously established countries such as the United States, Canada, and Western Europe. The advantages of outsourcing to emerging regions are clear: reduced costs, faster, more successful subject recruitment, and access to larger numbers of qualified patients. In addition, the spectrum of diseases in many emerging countries has grown to include many diseases prevalent in more developed countries. 

The challenge remains primarily in addressing regulatory differences, and overcoming linguistic and cultural barriers. Foreign sponsors have the additional responsibility of ensuring that international ethical standards are maintained. By taking language, culture, and socioeconomic factors into account, sponsors are also ensuring that the public image of clinical research in that country will remain positive. Ultimately, providing cutting edge treatments and helping to improve healthcare in emerging regions is mutually beneficial. In addition, these countries are becoming important new markets for biopharmaceutical products. However, in order to overcome present barriers in global trials, companies must establish a local presence; work with reputable investigators and sites; and partner with language service providers and CROs that have experience in a particular area. 

Director of Biotech and Pharma Research at Language Connections, 2001 Beacon Street, Boston, MA, e-mail: 

 is President at Global Health Education Foundation, Habsheim, France, e-mail: 

*To whom all correspondence should be addressed.

 1. Food and Drug Administration, "Office of International Programs: China and India," 

http://www.fda.gov/AboutFDA/CentersOffices/OC/OfficeofInternationalPrograms/default.htm

 2. Tufts Center for the Study of Drug Development, "Outlook 2009," 

http://csdd.tufts.edu/_documents/www/Outlook2009.pdf

 3. A. Karim and S. Salim, "Globalization, Ethics, and AIDS Vaccines," 

http://www.columbia.edu/itc/hs/pubhealth/p9408/readings/abdool_karim_2000.pdf

 4. A. Küçükdeveci, et al., "Issues in Cross-Cultural Validity: Example From the Adaptation, Reliability, and Validity Testing of a Turkish Version of the Stanford Health Assessment Questionnaire."

http://onlinelibrary.wiley.com/doi/10.1002/art.20091/full

 5. E. E. Teh and C. I. Hasanah,"Validation of Malay Version of Geriatric Depression Scale Among Elderly Inpatients," (2004), 

 6. Parliamentary Assembly Consiel d l'Europe "Endangered Uralic Minority Cultures," (September 25, 1998), 

http://assembly.coe.int/Mainf.asp?link=/Documents/AdoptedText/ta98/ERES1171.htm

Articles

With more clinical trials conducted overseas, sponsors are facing new obstacles.

Language & Culture in Global Clinical Trials

Due to the cost of developing biopharmaceutical products and problems with adequate subject recruitment for clinical trials in the United States and Western Europe, outsourcing clinical research in newly emerging regions is increasingly common. Although the most dominant emerging regions are primarily countries in Latin America, Central and Eastern Europe, and Asia, some countries in Africa are also becoming prominent locations. 

Past concerns about inadequate infrastructure and socio-political and economic problems in many parts of Africa have impeded growth in clinical research in the past. However, changing requirements such as patient diversity and the need for greater subject numbers in clinical trials in parallel with improved clinical research environments in some African countries, such as South Africa, have resulted in notable growth in clinical research in the region. 

Two factors distinguish South Africa from other countries in Africa: It's the most economically developed African country and it has established better regulatory standards for conducting clinical trials. However, several factors are responsible for its clinical research growth. 

Firstly, South Africa's total population is nearly 48 million, which provides a large, diverse patient population. Secondly, the majority of subjects enrolled in clinical trials have not received any previous treatment for their disease, either because it is not available to them or they cannot afford it. These factors greatly facilitate subject recruitment and help meet diversity requirements. In addition, lower costs for clinical research and lower risk of litigation make South Africa attractive for foreign companies outsourcing clinical trials. 

Although clinical research has been established in South Africa for a number of years, from 1997 to 1998 there was a 40% increase in total clinical trial activity due primarily to highly effective recruitment and retention rates.

  Recently, the most significant growth in clinical research occurred in disease areas prominent in South Africa, including HIV/AIDS, tuberculosis (TB), malaria, cancer, and diabetes. In addition, multisite trials in HIV, dermatology, hematology, asthma, chronic bronchitis, and pediatric and adult pain studies are becoming increasingly common.  

The number of trials conducted in South Africa has been growing exponentially over the past couple of decades across a wide range of therapeutic areas. According to the Beare Pharmaceutical Industry Report on South Africa, in the year 2001 approximately 400 studies were conducted. This number has continued to grow due to highly successful recruitment rates among patient populations and an improved regulatory environment.  

But despite South Africa's satisfactory clinical research environment, there are many vulnerable populations that live in great poverty and have little access to any medical care. Many of these individuals are poorly educated and tend to accept authority without question. This raises ethical issues when obtaining informed consent.  

In addition, it is not surprising that the focus on clinical research has been on infectious diseases, particularly HIV/AIDS, TB, and malaria, as large numbers of the country's population are greatly affected by these diseases. However, because many are extremely vulnerable, such as the large number of HIV pediatric cases, improved regulatory measures to protect these individuals must be implemented. 

Furthermore, language and cultural differences between ethnic/racial groups contribute additional barriers that must be taken into account. Taking greater measures to maintain international ethical standards particularly among vulnerable populations in South Africa will help pave the way for improved clinical research in other African countries. 

HIV epidemiology and clinical studies are especially prevalent in South Africa due to the growing epidemic of HIV/AIDS. At the end of 2007, 5.7 million inhabitants were living with HIV/AIDS,

  one of the worst AIDS epidemics in the world. As a result of these alarming statistics, in 2000 the South African government implemented an HIV Vaccine Action Campaign in an attempt to control the epidemic. 

Currently, 60% of the world's HIV/AIDS infected people are in Africa, and 59% of all infected individuals are women.

  Because of the high incidence of mother to child transmission, as of September 2008, South Africa's Minister of Health announced a full-fledged commitment to the prevention of HIV transmission to children. 

The first large-scale study to evaluate a candidate HIV vaccine on the African continent was recently announced by study collaborators in the United States and South Africa. The trial involves up to 3000 participants at five sites throughout the country and is expected to continue for four years.

  In previous Phase I and II trials, the vaccine was found to be safe and effective against HIV in more than half of the subjects tested. There is much hope that a safer and more effective vaccine will help control the exponential growth of this terrible epidemic. 

After eight years of research, one South African developed HIV vaccine is to become the first African vaccine to undergo human clinical trials in the United States.

  Results could take between five to eight years, however, the accomplishment of an undeveloped nation such as South Africa to develop a candidate vaccine and undergo clinical trials is already a milestone. If successful, the impact on the HIV/AIDS epidemic in Africa could be very significant. 

In 2006 the World Health Organization (WHO) ranked South Africa fifth among the world's 22 countries most burdened by TB. The incidence of TB has increased significantly in South Africa in parallel with the HIV/AIDS epidemic. According to the 2006 USAID Infectious Diseases Report on South Africa, up to 60% of adult TB patients are HIV-positive.

  Furthermore, TB is one of the principal causes of HIV-associated deaths among HIV patients. 

However, since the emergence of the HIV epidemic, the Directly Observed Therapy Strategy known as DOTS has failed to contain the spread of TB, particularly in southern Africa. Furthermore, progress in developing a treatment against multidrug resistant strains has been relatively slow. 

To conduct large scale Phase III TB vaccine trials and improve the infrastructure for research in South Africa, in 2007 Denmark's Medicon (in collaboration with Aeras Global TB Vaccine Foundation) trained 9000 South Africans in clinical research methods. This effort has facilitated clinical research in South Africa in all therapeutic areas.

Of the several potential TB vaccines being developed for clinical trials, one candidate is currently undergoing Phase II trials in South Africa. This particular vaccine is the most advanced of a new generation of preventive TB vaccines, and is being tested in a Phase IIb proof-of-concept trial at the University of Cape Town. The vaccine will be given to children who have been immunized with the BCG vaccine at birth in order to improve the level of immune protection. This is the first proof-of-concept trial of a new preventive TB vaccine in infants after many years, and is part of an effort by the South African Tuberculosis Vaccine Initiative.

Malaria is endemic in the low-altitude areas of the northern and eastern parts of South Africa, with seasonal transmission. The renewed increase in the incidence of malaria was a result of a ban by the West on the pesticide DTT in the early 1970s. Attempts to develop a vaccine that prevents infection have been unsuccessful, although there has been considerable progress over the past 25 years. 

Approximately 90% of malaria-related deaths occur in sub-Saharan Africa, and the majority of malaria casualties are children under age five. Because malaria infection in Africa can be fatal, the incentive for developing a successful vaccine that provides long-lasting immunity is great. 

The final phase of testing for "the world's most advanced malaria vaccine candidate" was recently initiated with five infants from Tanzania. Over the next few months, 16,000 children under the age of two will receive this malaria vaccine in several African countries, including South Africa. The successful completion of a Phase III trial would make the vaccine available possibly by 2012.

A safe and effective children's vaccine for malaria prevention would greatly reduce malaria infection in South Africa, where according to the WHO most of the 1 million people killed by malaria are less than five years old.

South Africa's relatively well-developed infrastructure and compliance with ICH-GCP guidelines are two factors that have contributed to the country's growth in clinical research relative to other countries in Africa. In 2000, a South African Good Clinical Practice (GCP) guideline was published by the South African Department of Health—a stricter version that strengthened the existing requirements was later published in 2006. 

Despite the fact that approval processes are somewhat lengthy, currently averaging 12 to 14 weeks, review and approval by the Medicines Control Council (MCC)

  responsible for scientific, medical, and ethical issues relating to clinical trial applications in South Africa is fairly consistent. Other related agencies include the nonprofit organization South African Clinical Research Association (SACRA) and the local Industry/Regulatory Task Group (IRTG). 

In 2001, the WHO's Regional Committee for Africa expressed concern that some health-related studies undertaken in the region were not subjected to any form of ethics review.

  There are several examples of ethically compromised clinical studies that have been conducted in South Africa in the past. One such study is a breast cancer study conducted by Werner Bezwoda, an oncology/hematology professor, on women at Baragwanath hospital in South Africa in 1995. A review revealed that no patient consent or ethics review were provided during the course of the clinical trial.

Although some past studies have not met adequately with international standards, more recent legislative changes have been put into place. In addition to the requirement for ethical standards, there are additional requirements specific to conducting clinical trials in South Africa. 

In 2005, the Department of Health released a national guideline outlining ethics in health research in South Africa requiring that Ethics Committees be "representative of the communities they serve and increasingly reflect the demographic profile of the population of South Africa." These guidelines, similar in principle to the International Conference on Harmonization for Good Clinical Practice guidelines (ICH GCP), specify in greater detail the requirements for diversity, demographic representation, and occupational identity specific to South Africa.

The issue of ethical informed consent practices in South Africa is a controversial one. Limited education, poverty, inadequate protection of human rights, discrimination on the basis of health status, and limited access to preventive care and treatment options are all contributing factors. 

Although there are significant improvements in the quality of clinical research, particularly involving ethical considerations, there are certain important aspects of the population that must be taken into account. These include political and socioeconomic factors, illiteracy, language barriers, and cultural differences among patient populations. 

 South Africa is a middle-income country with severe economic disparities. The majority of the population is categorized as socioeconomically low status and 50% of South Africans live below the poverty line.

  Almost two decades after the end of apartheid, vast racial inequalities still exist. Many South Africans continue to be underserved and disadvantaged because of their race and/or ethnicity, especially regarding health care.

  An awareness of these issues is vital to maintaining the standards appropriate for international research. Vigilance on the part of sponsors to ensure that past prejudices do not interfere with current studies is crucial. 

 Recently, a new "speaking book" has been developed to help inform less-educated subjects of the benefits and risk factors involved in clinical trial participation. Some of the health-related topics covered include HIV infection, tuberculosis, and malaria. The advantage of these speaking books over conventional methods is that the books provide a verbal explanation accompanied by visuals rather than a written text.

  Considering the illiteracy rate among much of the clinical trial participants in South Africa, this new method will greatly improve subject understanding and help raise ethical standards. Although the reported literacy rate among adults in South Africa is 86%, this rate varies significantly among different ethnic/racial populations.

 There are 11 official languages, the most common are English and Africaans. Each of the 11 includes a number of regional dialects and variants. Nine of South Africa's official languages (all except Afrikaans and English) are Bantu languages. Bantu languages are a large branch of the Niger-Congo language family, which is represented throughout much of sub-Saharan Africa. 

Because of British rule, English is the most common language of the government, business, and scientific communities. However, according to the 2002 Pan South African Language Board survey, only 22% of the population has an adequate understanding of spoken English, such as that used in political speeches. Furthermore, different regions in South Africa predominantly speak distinct languages, including Zulu, Sotho, and Africaans, depending on the dominant influences and ethnic groups. 

Informed consent and other patient-related materials must be translated into the native language of the patient. In South Africa this is not a simple issue. Not only are there several official languages but there are not always well-established translation equivalents for standard clinical trial terminology. For example, one South African study concluded that language may create barriers to informed consent by prospective research participants when there are no local words for "randomization" or "placebo."

 Informed consent concepts are interpreted differently in different parts of the world. In traditional, rural African communities for example, a form of "communitarianism" dominates.

  In this context, research is an altruistic endeavor that benefits society. Western ethical consent guidelines that emphasize the individual over the community may not apply in this type of environment. 

Economical development and regulatory standards make the country a logical choice for trials.

South Africa Today

Several countries in Central and Eastern Europe, Asia, and Latin America are among the most prominent new locations for outsourcing clinical trials. In the past, few clinical trials were conducted in Latin America due to a number of factors including poverty, political instability, and lack of infrastructure. Most importantly, however, regulatory requirements did not meet with international standards. Recently, governments in this region have made considerable efforts to improve their health care regulations, including the gradual implementation of ICH-GCP guidelines in clinical research.

Photography: Odilion Dimier,  PhotoDisc, Getty Images Illustration: Paul A. Belci			

Argentina currently has the most advanced regulatory legislation in Latin America.

  Another problem that is gradually being overcome is the lack of adequate patent protection in Latin America. Between 1991 and 1995, new patent protection laws were established in several Latin American countries, including Peru, Argentina, Mexico, Chile, and Brazil.

  This has further facilitated the growth of clinical research and development in this region.

Despite the advantages of outsourcing clinical trials, language remains a major issue, even in Latin America, where one language dominates. Spanish is officially the main language, with the exception of Portuguese in Brazil. This reduces the complications that arise in regions where translation of regulatory documents must be done in multiple languages. The use of a common language also reduces language barriers in conducting multinational clinical trials, particularly compared to other newly expanding regions such as Eastern Europe and Asia.

However, the issue of language in Latin America should not be underestimated. For one thing, there are several regional differences in the Spanish spoken. Furthermore, these differences among Latin American countries can introduce barriers to research if they are not addressed.

In addition, differences in cultural attitudes and medical practices must also be taken into account. While there are many advantages to conducting studies in this region, successful clinical trial management requires that language and cultural differences be taken into consideration.

Among emerging research markets, Latin America is becoming a desirable location for conducting clinical trials for a range of reasons, mostly related to subject recruitment.

  Latin America is the world's fourth largest clinical trials market. The concentration of the region's population of 500 million people in urban areas (where 70% of the total population lives) facilitates rapid subject enrollment. The four largest cities in Latin America—Mexico City, Rio de Janeiro, Sao Paulo, and Buenos Aires—are among the largest cities in the world, accounting for over 40 million people.

Due to such large numbers of drug-naïve subjects, their proximity to urban centers, the high success of subject enrollment and retention, and reduced costs for clinical research, Latin America is understandably playing a growing role in global clinical trials.

Mexico, Brazil, and Argentina are the three most established Latin American countries in clinical research due to improvements in their regulatory legislation. Other countries in Latin America are evolving their health care-related legislation, and thus regulatory environments are continually improving.

Currently, Argentina, Brazil, Mexico, Chile, Colombia, and Peru are the primary Latin American countries conducting clinical trials. This is in large part due to the fact that their combined populations account for approximately 80% of the region's total population,

  greatly facilitating their ability to meet subject enrollment requirements. The importance of these large populations in recruiting subjects for multinational, multicenter trials, which are increasingly common particularly in Phase III, reflects the expansion of clinical trials in the area over the last decade.

The primary reason that recruited subjects in Latin America are more eager to enroll in clinical trials is that for much of the population no other treatment options are available. Due to the fact that many trial subjects come from lower economic backgrounds, they do not have the resources or access to current and effective medical therapies available in more developed parts of the world. Thus, the ability to participate in a clinical study may be the only opportunity to receive treatment for their particular ailment, and following regulatory approval, such therapies may become more readily available.

In addition, the number of qualified clinical investigators is increasing to meet the growing demand in clinical research in the region. The advantages of conducting clinical research in Latin America are clear, however, there are important barriers that must be overcome.

With the previously noted exception of Brazil, all key regulatory documents involved in Latin American clinical trials must be translated into just one language, facilitating the use of EDC methods as well as translation procedures. However, one must keep in mind that there are regional differences in locally spoken Spanish as well as important cultural differences among Latin American countries.

Although they may share a common language, Latin American countries have subtle linguistic differences that can result in miscommunications if they are not properly addressed. These regional differences, or dialects, are influenced by the indigenous languages of Latin America, as well as by the native languages introduced by immigrants from other countries such as Germany, Italy, and France.

For example, many words from the original indigenous languages in each region have permanently replaced certain Spanish words. Although the educated populations including clinical investigators may speak Castilian Spanish, and even English, many patient populations more commonly speak their own regional Spanish.

In spite of the fact that many languages of the native Latin American people are no longer used, some still maintain their influence. The most widely spoken indigenous language, Quechua, is the native language of at least 10 million people across several Latin American countries including Brazil, Colombia, Argentina, Bolivia, Ecuador, and Peru, where it is one of the official languages.

The issue of language in Latin America is more complex than one might expect. Therefore, accurate translation of study documents by native Latin American speakers from each country plays an important role in the success of trials in the region. Most importantly, to ensure informed and voluntary consent, patient informed consent forms must be translated into the regional Spanish of the participant. In addition, all patient-related study documents such as diaries must also be translated into local regional Spanish.

Since certain populations in Latin America are especially vulnerable, due to poverty and illiteracy, efforts to protect their rights have been evolving. Particularly in the case of indigenous subjects, it is common procedure in several Latin American countries to submit study protocols to local ethics committees following subject enrollment.

Translation of such patient documents by native localization experts is the best way to ensure the patient's clear understanding of the study in which they will participate. In addition to patient-related documents, all regulatory documentation for clinical trials in Latin America must be translated into Castilian Spanish for local regulatory authorities. In Brazil, the same holds true for Portuguese translations.

In addition to language barriers, there are cultural and socioeconomic factors that have been shown to directly impact clinical research in bilingual studies in the United States, as well as research conducted in emerging markets. One such study conducted in 1995 and in 1999 involving less educated, U.S. Spanish-speaking subjects reported problems with compliance because of the patients' inability to follow written instructions effectively.

Similar problems have been reported in Latin America, where there are several indigenous populations and literacy rates are reportedly low among some of them. The indigenous populations of Latin America account for approximately 40 million people, percentages varying among different Latin American countries.

  Moreover, because of geographic diversity and influences from different ethnic groups throughout Latin America, there are some important cultural differences. These differences must be well understood as they can negatively affect clinical research. For example, a patient who is participating in a study while practicing herbal medicine may fail to report such use at the time of a study due to cultural attitudes. Several indigenous populations have traditionally used herbal therapies throughout Latin America, however, they may not report herbal practices because of the marginalization of indigenous herbal medicine in Latin America.

Despite specific population differences among Latin American countries, there are some common traits that affect clinical research in this region. Cultural attitudes, for example, which influence medical practices and the manner in which information is communicated can greatly affect how clinical research is conducted.

In contrast to U.S. patients, Latin American patients tend to rely primarily on the recommendations of their physician when making decisions about their health. This can lead them to enroll in a study without questioning. Thus, in addition to issues of language and literacy, informed consent can be adversely affected by cultural issues.

Furthermore, revealing a patient's complete diagnosis prior to conducting a study is not always common practice in many Latin American countries. This is especially the case in dealing with terminal illnesses such as cancer. Many times the involvement of the family is an important factor in the treatment of the patient, and full diagnosis may only be given to the patient's family members. Thus, the extent of information disclosed to a subject during a study may also be influenced by culture.

According to a study commissioned by the U.S. National Bioethics Advisory Board, in many Latin American countries there is a general distrust of signing documents. This was not because of illiteracy, as people in countries with higher literacy rates such as Argentina also exhibited this behavior, but rather a developed mistrust of authority as a result of past experiences with oppressive regimes. These cultural attitudes were found to interfere with the signing of informed consent forms, and as a result new methods were adapted for ethically obtaining informed consent.

The outsourcing of clinical trials to Latin American countries has steadily increased over the last 10 years, primarily due to the demands for greater subject enrollment. As Latin American governments continue to improve their health care and regulatory environments, this region will continue to be an important location for clinical research.

In addition to regulatory issues, many factors play a role in the success of clinical research at international sites, including differences in medical practices, language, and culture. The differences between Latin American countries must be well understood and taken into careful consideration when conducting clinical research in this region. The process of informed consent, in particular, relies on a better understanding of cultural and linguistic differences.

The success of clinical research in Latin America is therefore necessarily dependent on language and cultural barriers being overcome. Proper clinical trial management requires that expert translation and localization strategies be implemented at all stages of clinical research. 

, MS, is director of biotech and pharmaceutical research at Language Connections, 2001 Beacon Street, Boston, MA 02135, email: 

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Undertaking clinical studies in this emerging region requires first overcoming natural barriers.

Karen Politis Virk

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