Faiz Kermani, PhD, is a budgets, proposals, and marketing executive with Chiltern International Limited, a CRO in Slough, Berkshire, UK.

Faiz Kermani, Ph.D

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

Like other major business sectors, the pharmaceutical industry is under constant scrutiny regarding the way it operates. Since there is an ever-continuing rise in interest by the media and public in the type of health care service being offered, pharmaceutical companies cannot avoid being caught up in the discussion of such issues. Medicines produced by the pharmaceutical industry are a key part of the delivery of an effective health service. Media coverage of the pharmaceutical industry's activities has often been negative, and whether they like it or not companies have to pay greater attention to their public image.

Public perception cannot be ignored, particularly since health care is a major election issue and voter opinion will have an impact on a government's policies. For example, in 2002 the U.S. seniors group AARP accused some pharmaceutical companies of using "front" groups that purported to represent the elderly and released messages that favored the industry's point of view on issues such as pricing.

  These types of claims often result in major press coverage and can be highly damaging to the pharma industry. This is particularly unfortunate, since such publicity overshadows the pharmaceutical industry's vital role in researching and developing medicines.

As the pharmaceutical industry runs clinical trials to develop its products, it must engage the public and show them that it is working in their best interests. Otherwise, they will not volunteer to participate in trials, which will effectively hamper the development of new medicines.

In recent years, the concept of corporate social responsibility (CSR) has grown in importance. CSR is often discussed at the highest levels within companies, but there are a variety of interpretations as to what it means.

Issues such as respect for employees, environmental responsibilities, relationships with local communities, and fair trade with developing nations often feature as part of CSR.

  In truth, it is probably impossible to find a strict definition that suits all companies and their activities. CSR can be subjective, relying on interpretations of how commercial activities are perceived in terms of integrity, fairness, and respect for individuals.

As a business operates to generate profit, those advocating CSR are essentially asking companies to look beyond how their decision-making impacts on commercial activities and examine the effect on the society around them. This is no easy task, since an activity that generates money for the company could actually be perceived negatively in the strict context of CSR. 

Interestingly, the economist Milton Friedman believed that CSR was misguided, as the only responsibility of a business was to generate profit.

  However, this point of view is easily countered, since businesses depend on the society that surrounds them and their staff is influenced by what takes place outside their company's boundaries. Company staff members are also consumers who, like other patients, seek affordable medicines for themselves and their families. Furthermore, they will have concern for global issues such as improving health care in the developing world.

Recently, health care charities, pharmaceutical companies, and international not-for-profit organizations jointly signed an open letter to the G8 leaders calling for them to address health care issues affecting developing countries and provide incentives for the private and public sectors to work together in resolving the situation.

  Thus, those working in pharmaceutical companies should not have great problems identifying issues that are considered important by the public. 

Staff turnover in the pharmaceutical industry can be high, and if a company wants to retain talented people it must pay greater attention to the conditions in which they work. Replacing an experienced staff member is no easy task, and one company's loss can be another's gain. For example, when large pharmaceutical companies have down-sized, smaller biotech companies have often benefited from taking on the experienced people who suddenly found themselves in the job market. In many cases these individuals have thrived, as they have been able to apply their knowledge in an atmosphere free from bureaucracy.  

The term "human capital" has often been used as a means to assign value to staff within an organization, but although many senior managers can discuss such a concept, few are able to demonstrate to their staff that their work is truly appreciated. In fact, paying greater attention to staff value can be a huge asset to companies, as the best candidates in the job market will be attracted to work for a dynamic organization that takes care of its employees. Staff turnover can also be reduced because people feel as if they're part of a cohesive team.  

This process can be enhanced if a company has recognized CSR credentials, as staff members and job-seekers alike will view a company with credentials as standing out from competitors because of how it views its role in society. After all, they are themselves drawn from society and will be concerned about the same global issues as the general public. 

For example, the U.S. biotech company Genentech has won several corporate awards, which are undoubtedly an attraction for those seeking to work in the health care sector. Many of these awards are based on employee responses to independent surveys that focus on work conditions and external analyses of the corporate culture. In 2005, for the seventh consecutive year 

 magazine named Genentech one of the "100 Best Companies to Work For," and in 2004 it was named No. 1 Employer by 

  The company's image is enhanced even further by the fact that in spring 2005 Genentech was voted Top Corporate Citizen by 

 included it in their third annual list of corporate philanthropists in the Bay Area.

CSR is unavoidable in the modern business world, and the concept should be embraced rather than feared. The pharmaceutical industry has nothing to gain from the public taking a negative view of its activities, but everything to gain from demonstrating to them that companies are an essential part of health care. Without the pharmaceutical industry and the commercial forces that it harnesses in R&D, many drugs would not reach the market—but this is rarely discussed by the media. Equally, companies must look beyond commercial decisions and openly address the issue of affordability, as governments are increasingly shifting health care costs to patients. They must also demonstrate their commitment to staff if they wish to harness their talents over the long period required to develop new drugs. 

  budgets, proposals and marketing executive, Chiltern International, 

www.inpharm.com/External/InpH/1,2580,1-3-0-0-inp_intelligence_art-0-287636,00.html

2. R. Moynihan, "US Seniors Group Attacks Pharmaceutical Industry 'Fronts,'" 

bmj.bmjjournals.com/cgi/content/full/326/7385/351

3. F. Kermani and P. Bonacossa, "New Ways to Recruit Trial Subjects," 

www.actmagazine.com/appliedclinicaltrials/article/articleDetail.jsp?id=80333

4. T. Donaldson, "Defining the Value of Doing Good Business," 

news.ft.com/cms/s/748f21be-d377-11d9-ad4b-00000e2511c8,dwp_uuid=1d0ff528-c86c-11d9-87c9-00000e2511c8.html

5. Open Letter to the Leaders of the G-8 Nations, The Global Alliance for Vaccines and Immunization, 17 June 2005, http://

www.vaccinealliance.org/resources/PPPletter_17Jun2005.pdf

6. Awards & Recognition, Genentech, 2005, http://

www.genentech.com/gene/about/corporate/awards/index.jsp

CSR is in the best interest of the public at large...and the pharmaceutical company itself.

Why Corporate Social Responsibility Makes Sense

In recent years, the Asian pharmaceutical market has assumed considerable importance for global pharma companies. Its improving economic conditions coupled with a large and growing population offer opportunities for pharmaceutical companies in terms of product sales and R&D.

Japan is the most established Asian pharmaceutical market,

  but cost containment measures implemented by the government to slow health care spending have proved unpopular with the international pharmaceutical industry, and many companies have begun to look to additional national markets in the region. China has received the most interest in the media, largely due to the fact that its economy is growing at a tremendous rate and foreign firms in a variety of sectors, including pharmaceuticals, have invested heavily there. According to 

, since 1978 the Chinese economy has grown at an average annual rate of 9.4%.

South Korea is another Asian country that has attracted the attention of pharmaceutical companies, and the increasing popularity of the country for foreign businesses has largely gone unreported by the media. With a population of nearly 50 million and a GDP per head of around US$14,000, it represents an important Asian consumer base.

  To some extent, the media's enthusiasm for South Korea was dampened by the 1997 financial crisis, which severely dented the country's economic prospects and led to many foreign investors selling their assets.

  According to The Economist Intelligence Unit, although South Korea's economic recovery may be uncertain, the country's foreign-exchange reserves of around US$200 billion make the likelihood of another financial crisis unlikely.

  South Korea's foreign-exchange reserves have been described as the second highest after Japan, among the 30 international member countries that make up the Organisation for Economic Co-operation and Development (OECD).

  From a pharmaceutical company perspective, the South Korean government's renewed focus on health care and demand from the population for new medicines is providing a long-term incentive for pharmaceutical companies to invest in the country. 

The growing interest in South Korea is highlighted by the decision to hold the 2006 International Conference on Pharmaceutical Medicine (ICPM: 

) in the capital Seoul. Representatives from a number of major pharmaceutical companies are on the organizing committee, and the conference is also being backed by the Korean Society for Pharmaceutical Medicine (KSPM: 

) and the Korean Society for Clinical Trials (KSCT: 

). The event will feature three plenary sessions, 11 symposia, and various training courses that will examine pharmaceutical medicine from global, technical, and functional standpoints. 

Following the 1997 economic crisis, the South Korean government attempted to repair the damage that the financial uncertainties had caused to the health care system and its funding structures. The National Health Insurance Act, brought in during 1999, aimed to integrate multiple insurance societies into a single insurer system and enhance the equity of financing for health care.

  Backed by temporary measures through the 2002 Special Act for Financial Stabilization of National Health Insurance, the government attempted to once again provide comprehensive health care services to the public.

The Health Insurance System of Korea is mandatory for Koreans living in the country except for some Medical Aid beneficiaries. In October 2003, it was estimated that the National Health Insurance (NHI) Program covered 97% of the population

  (see Figure 1). The Medical Aid Program, a Korean social assistance program, covered the remaining 3%, mainly belonging to low-income groups. The Ministry of Health & Welfare (MOHW) oversees the operation of the NHI program.

 Figure 1. Employees in the public and private sectors covered by the South Korean health insurance program and their dependents.			

In a 1999 survey carried out by CMR International, respondents from major pharmaceutical companies predicted that although China would become the Asian region of greatest commercial importance by 2005, South Korea would be the second most important Asian emerging market and that it would retain this market ranking in the long term.

  Furthermore, the respondent companies were carrying out an increasing number of clinical trials in these countries in order to satisfy the local regulatory authorities.

  Other reasons cited for carrying out clinical trials in South Korea included providing local physicians with experience of the product and generating additional data from postmarketing surveillance work.

  Interestingly, some of the respondent companies expressed the view that the requirement for them to carry out additional local clinical trials at the presubmission stage acted as a major barrier to the rapid registration of their product in South Korea.

  However, as these perceived barriers were also a feature of other Asian markets such as China, India, and Malaysia,

  these factors were not deterring companies from making further investments in South Korea. 

A major attraction for pharmaceutical companies has been the separation of medical prescribing and dispensing, which represented a key part of South Korea's health care reforms and began in July 2000.

  This process, whereby there was a shift from dispensing doctor to a retail pharmacy market was strongly resisted by physicians, who had traditionally derived a large proportion of their income from pharmaceuticals.

  According to a 2003 report by the U.S. & Foreign Commercial Service and U.S. Department of State, these measures appear to have benefited multinational pharmaceutical companies. Since the prescribing changes were finally introduced, multinationals have expanded their share of the total South Korean pharmaceutical market from 23% in 2000 to 26% in 2001, and to 29% in 2002.

  The report predicted that by the end of 2003, multinationals would achieve a 31% pharmaceutical market share,

  and a more recent assessment has suggested a market share of 70% by 2005.

There have been frequent complaints by foreign pharmaceutical companies about inadequate data protection measures, excessive requirements in the area of clinical trials for their products, and the lack of transparency of the South Korean pharmaceutical pricing system, as they believe that current procedures favor domestic companies.

  Both the Pharmaceutical Research and Manufacturers of America (PhRMA), which represents U.S. companies, and The European Federation of Pharmaceutical Industries and Associations (EFPIA), which represents European companies, have lodged official complaints against South Korea's discriminatory trade practices and market access barriers to foreign companies.

  Nevertheless, there remain considerable opportunities for foreign companies due to the strong demand from the population for new medicines.

  According to OECD estimates, pharmaceuticals account for around 30% of health care spending in South Korea, which is considerably higher than the OECD average of 16%.

While South Korea's government has introduced reforms to expand health care coverage and control rising health care expenses, it has so far been unable to achieve this goal. Ministry of Health and Welfare (MoHW: 

) budget figures show that in 2001 despite the reforms, spending on reimbursed drugs rose 25% to approximately $3.7 billion (local currency: Won 4500 billion).

  As prescribing practices changed, it was noted that patients were keenly aware of the identity of the product being prescribed, so doctor's often felt obliged to recommend a multinational company's brand.

  The preference for foreign brands was reflected in the fact that seven of the top 10 products sold in South Korea during 2001 were from multinational companies or their licensees.

In 2003, the South Korean pharmaceutical market was valued at $4.6 billion and was predicted to grow at an average annual rate of 5% over the next several years.

  Recent analyses have shown that despite being around a tenth of the size of the Japanese pharmaceutical market, South Korea has consistently outpaced its Asian neighbor over the past few years.

  At present, despite the concerns that many foreign companies have about the South Korean regulatory and pricing environment, the pharmaceutical market is proving profitable for those companies that have invested in the country. 

The implications of global clinical development

As well as growing in importance as a pharmaceutical market, South Korea has also become an R&D base for companies. In particular, both foreign and domestic companies are running a number of clinical trials in the country. In 2000, the Korean Food & Drug Administration (KFDA: 

) registered 34 clinical trials on its database, of which 29 were defined as local trials and five as multinational.

  By 2002, this number had increased to 55 clinical trials, of which 38 were registered as local trials and 17 as multinational clinical trials.

  In 2003, the KFDA recorded 107 clinical trials on its database, of which 67 were local and 30 multinational.

As clinical trials progress to involve new areas of the world, there is often a focus on the technical expertise available in these regions to carry out studies to international standards. However, equally important is the existence of an ethics system that ensures subjects are well cared for and looked after and that they participate in studies of their own free will.

 In recent times, there have been calls by a number of industry observers to ensure that such systems are in place around the world. Their concerns are that in the drive to reduce costs and enroll patients rapidly, companies may not sufficiently highlight how ethical standards will be maintained.

  There are difficult questions to answer in how best to involve subjects in clinical trials when operating in emerging markets, as commercial factors are also involved, and the discussion can become emotive.  

Current media coverage of how pharmaceutical companies operate in emerging markets is often negative,

  and it is in the industry's interests to counteract these reports so that there can be no doubt that ethical standards will be maintained. For example, in 2003 a UK television program heavily criticized the activities of the pharmaceutical industry around the world, including in South Korea.

  The program provoked a furious reaction from the pharmaceutical industry, which accused the producers of failing to provide balanced reporting of the issues and completely ignoring the important research that was involved in developing a new drug.

  Following the broadcast of the program, the pharmaceutical industry countered with a robust defense of its work.

In more established markets there have been a number of instances in which patient participation in clinical trials has been identified as contributing to advances in medical research and treatments, even when taking into account the commercial gains for the companies involved. If companies wish to gain local support in emerging markets, then it will be important to demonstrate the advantages that their trials can bring to populations in these areas. South Korea has placed considerable emphasis on building its biomedical capacity in line with the global focus of drug development, and there is a strong desire by those involved for a better ethics system to be in place so that clinical trials can be run to the highest possible standards.

  Many in government and academic circles would like to see South Korea become a favored region in Asia for companies to conduct clinical trials. 

There have been few medical research scandals in South Korea, and patients are considered to be generally well protected and cared for in biomedical research.

  Despite this good track record, the South Korean medical community and pharmaceutical industry have expressed a strong desire to identify any shortcomings of the current Institutional Review Board (IRB) system and have lobbied the government to make improvements. They believe that without improvements, the current IRB setup could be perceived as a barrier to biomedical research in South Korea.

Starting in the 1980s, a number of IRBs were set up in South Korea, and their importance was confirmed in 1995 when Korean Good Clinical Practice (KGCP) guidelines, which stated that clinical trials had to abide by IRB regulations, were introduced.

  These IRBs are widely considered to have been a positive force in improving the standards for clinical research in South Korea.

  In 2001, the South Korean government revised KGCP in line with ICH-GCP, the international ethical and scientific quality standard to ensure that clinical trials involving human participants are designed and carried out in an ethical manner.

  These revisions necessitated the establishment of various legal structures that would ensure that South Korean IRBs could operate to international standards.

Nevertheless, IRBs are still considered a new concept in South Korea and, as highlighted in a 2003 editorial in the 

 there remain differences of opinion in how they should operate and the types of representatives who should be involved in their activities.

  Many South Korean medical institutions reportedly do not yet have IRBs to guide them in their research.

  International standards require IRBs to be independent, transparent, and competent in their assessments and decision-making.

  The editorial stressed the importance of IRBs being independent of investigators and suggested that they should include at least one nonmedical person and another unaffiliated to the institution.

  There is also the worry that given the volume of biomedical research being carried out in South Korea, the IRBs are not yet ideally structured nor experienced enough to handle the increase in workload.

In 2002, the Korean Association of Institutional Review Boards (KAIRB: 

) conducted a survey of IRBs operating in the country. Out of 74 IRBs approached, 63 responded to the survey.

  Around 80% of the respondent IRBs confined the scope of their evaluation to the clinical evaluation of drugs or medical devices, but did not address other areas of research involving human participants.

  The limited scope of review was considered to be a serious problem by KAIRB.

  The IRBs appeared to limit their work to those areas that they were legally obliged to review rather than extending them to cover other areas of research involving human participants.

  This is an area where KAIRB would like to see a tightening up of the process. Interestingly, these improvements to the IRB system may come through South Korea's growing interest in stem cell research. As this is a controversial area of research, the government's Ministry of Science and Technology has requested that any projects it funds must have all aspects of their work reviewed by an internal ethics committee and the IRBs of the institutions where the work is to be carried out.

The survey also revealed that many medical institutions did not have an identifiable IRB, and that when they did they often lacked independence. In 91% of the IRBs, the president of the hospital appointed the members, and in two-thirds of cases, the president appointed the IRB chairman or took the position themselves.

  This represents a fundamental weakness in the setup; because the IRB members work for the very institution conducting the research they are reviewing, there is a potential conflict of interest.

  KAIRB warned that this could mean that individuals felt influenced in their decision-making by those senior to them in the institution and by researchers they collaborated with.

 An additional problem is that few IRBs were considered to be representative in terms of gender and professions. In particular, it was noted that 57% of respondent IRBs did not have a layperson as a member and that 60% did not have members from outside the institution concerned.

According to KGCP, IRB members and clinical investigators were required to have sufficient training and education to carry out their roles. However, less than 20% of institutions surveyed by KAIRB were providing education for their IRB members, and only 10% were doing so for clinical investigators.

  Although some institutions ran annual workshops on human biomedical research, there was a lack of a specified curriculum to educate IRB members and clinical investigators on ethical research practices.

While KAIRB does not claim that its 2002 survey data are complete and without error, it does conclude that there are identifiable weaknesses in the current IRB system that must be addressed.

  It noted that some IRBs were more experienced than others in dealing with the ethics of biomedical research, and that many were aware of their own limitations and had already identified areas for improvement.

  Any such improvements to the IRB system will take time and will be furthered through the establishment of regional, national, and international networks so that information can be easily exchanged. In fact, one of the reasons KAIRB was originally founded was to act as a conduit for improvements in the South Korean IRB system so that it met international standards. KAIRB was set up under the auspices of the South Korean Academy of Medical Sciences and has members in hospitals, research institutes, pharmaceutical companies, and health authorities.

  It runs national conferences to encourage discussion among its members, and hopes that its 2002 survey will act as a means to benchmark improvements to IRBs in the future. 

The KFDA is the regulatory agency for food, drug, and other cosmetic products in South Korea and instigates guidelines and procedures concerning medicinal products, medical devices, cosmetics, and biological products (see Figure 2). The KFDA is also involved in ensuring the safety and effectiveness of medicines, regulating controlled drugs, and approving manufactured and imported medical devices.

There are several departments within the KFDA with different areas of responsibility, among them, the pharmaceutical bureau (comprising five divisions), which is involved in developing drug safety plans for medicinal products, medical devices, and cosmetics, and approving manufactured or imported drugs and biological products. The agency also has several provincial offices with responsibility for conducting food and drug surveillance in its regional laboratories. 

With regard to clinical trial applications, an initial consultation is recommended by the agency, which can vary in terms of time and content depending on the type of product under investigation. Following consultation, the sponsor then submits the application dossier, which should include essential documents such as the protocol, investigators brochure, CMC section, and preclinical data. The KFDA has shortened regulatory approval timelines to bring them more on a par with those in North America and Europe, and consequently, sponsors can now expect authorization within 30 days of receipt of the clinical trial application. The overall approval procedure in South Korea is further expedited due to the possibility of making parallel submissions to both the ethics committees and the competent authorities, with the import permit issued along with regulatory approval. Nevertheless, time must be allocated to ensure that the full CTA dossier is fully translated into Korean prior to the submissions.

Table 1. Problems identified in the South Korean review systems			

Once the application is received by the KFDA, assessors in the appropriate departments review the dossier. This assessment is normally done within the Pharmaceutical Safety Bureau, which reviews all data associated with the CTA in compliance with national standards. 

For marketing authorization applications, in contrast to the competent authorities in North America and the EU, the KFDA has historically required repetition of clinical trials already performed outside of South Korea for products that have been developed within a reasonably short time frame. For the sponsor, this has inevitably resulted in increased overhead and caused unwanted delays in the registration process. The KFDA, however, is making imminent plans to amend the existing requirements and bring them more in line with ICH guidelines. Timelines for marketing authorizations vary depending on the product in question, but on average authorization takes approximately 70 days. 

At present, the KFDA is poised to make further changes to their pharmaceutical regulations and an effort is currently being made to publish an English version of their present legislation on the KFDA Web site. 

Although multinational pharmaceutical companies dominate the market in South Korea, the domestic industry is highly active. Most domestic companies have been involved in the production of low-cost generics, but they are attempting to engage in more innovative R&D, and several have sought partnerships with international companies.

There are currently around 79 local pharmaceutical companies, and they have 86 research laboratories. R&D personnel represent nearly 12% of the total workforce. In 2002, domestic companies were involved in 90 research projects, with most of these falling into the cancer, anti-infectives, metabolic diseases, and immunology categories.

  Despite running these projects, when surveyed, 97% of local companies viewed partnerships with global organizations as being of benefit to their commercial objectives.

To better coordinate the activities of the domestic pharmaceutical industry and boost its standing, the Korea Drug Research Association (KDRA) was established in 1986.

  The KDRA is a nonprofit organization that represents its member companies and promotes joint projects between industry and academic institutes.

  The KDRA manages the Korea New Drug Award scheme to reward innovation, and it has set up the PharmaTech Business Center to advise companies on technology transfer issues. 

One of the major successes for the domestic industry was SK Chemicals's 1999 local launch of Sunpla, a third-generation platinum complex anticancer drug.

  Another high point for the domestic industry was Daewoong Pharmaceuticals's 2001 launch of Easyef (epidermal growth factor) for the treatment of diabetic foot ulcers.

  Easyef is now undergoing international trials; if the drug is eventually launched in a foreign market, it will be a major boost for domestic companies. 

Another South Korean company, Choongwae, has also benefited from implementing an ambitious R&D strategy. In 2002, Choongwae launched Balofloxacin (Q-roxin), an orally active fluoroquinolone antibiotic.

  The compound had originally been developed by Chugai and Ciba for the treatment of respiratory infections, but due to a lack of efficacy and the changing focus of Chugai's R&D, the project was discontinued in 1995.

   Following Phase II trials, Choongwae bought the rights for the drug and successfully carried out Phase III trials. Balofloxacin was approved by the Korean FDA in December 2001 for urinary tract infection.

The KDRA believes that these examples demonstrate how its domestic member companies are slowly beginning to overcome the initial technical problems associated with drug development, and it expects productivity to increase.

This Asian market holds great potential for the future, including possible collaborations with global pharma partners.

Faiz Kermani, Ph.D

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