Rory Gallagher

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.

  According to the KDRA, a total of eight new, locally researched drugs have been launched on the domestic market following approval from the KFDA. Furthermore, it describes 21 projects as being at various stages of clinical development, with another 47 at the preclinical stage.

Another area where South Korea wants to improve its position is biotechnology, and it has launched a number of schemes to encourage research by domestic start-up firms. In 2005, it launched a long-term strategy known as "the Bio-Star Project." Managed by the South Korean Ministry of Commerce, Industry and Energy (MOCIE: 

), this 10-year plan will result in a total of US$253 million being invested in the domestic biotech industry, and will feature cooperation between the government and business investment community.

  The Bio-Star Project will aim to aid those interested in commercializing biotech projects and will provide assistance for the different stages of the R&D process, including clinical development.

 The government has recognized that much of R&D investment is accounted for by clinical testing, and therefore seeks to provide funds for specialized contract research organizations in this field.

Despite high ambitions for its pharmaceutical and biotech sectors, South Korea faces a number of challenges in order to compete internationally.

  As multinational pharmaceutical companies already have considerable previous experience in developing and launching drugs internationally, they are in an advantageous position compared to their emerging South Korean counterparts. Furthermore, their R&D budgets dwarf those of South Korean pharmaceutical companies. South Korean pharmaceutical companies currently spend between 4% and 6% of their turnover on R&D,

  whereas multinational companies often spend a high double-digit percentage of their turnover on research. 

South Korean biotech firms face a similar problem. According to an analysis by the U.S. Commercial Service, in 2000, South Korea was ranked 14th globally in terms of total biotech R&D investment. At this time, South Korean government biotech R&D investment was estimated to be 1% of the equivalent in the United States and 10% of Japanese government R&D biotech expenditure.

For the moment, the best chances for the majority of domestic companies to internationalize their products lie in collaborations with foreign partners, as this will provide financial support and reduce the risks of drug development.

  Many domestic companies are already engaged in such ventures.

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